EP2029602A2 - Triazolopyrazinverbindungen zur behandlung von degenerations- und entzündungskrankheiten - Google Patents

Triazolopyrazinverbindungen zur behandlung von degenerations- und entzündungskrankheiten

Info

Publication number
EP2029602A2
EP2029602A2 EP07729660A EP07729660A EP2029602A2 EP 2029602 A2 EP2029602 A2 EP 2029602A2 EP 07729660 A EP07729660 A EP 07729660A EP 07729660 A EP07729660 A EP 07729660A EP 2029602 A2 EP2029602 A2 EP 2029602A2
Authority
EP
European Patent Office
Prior art keywords
triazolo
pyrazin
substituted
pyrazol
piperazin
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP07729660A
Other languages
English (en)
French (fr)
Other versions
EP2029602B1 (de
Inventor
Martin James Inglis Andrews
Paul Edwards
Mark Stuart Chambers
Wolfgang Schmidt
Juha Andrew Clase
Gregory Bar
Kim Louise Hirst
Angus Macleod
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Galapagos NV
Original Assignee
Galapagos NV
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Galapagos NV filed Critical Galapagos NV
Priority to SI200730288T priority Critical patent/SI2029602T1/sl
Priority to PL07729660T priority patent/PL2029602T3/pl
Priority to EP07729660A priority patent/EP2029602B1/de
Priority claimed from PCT/EP2007/055246 external-priority patent/WO2007138072A2/en
Publication of EP2029602A2 publication Critical patent/EP2029602A2/de
Application granted granted Critical
Publication of EP2029602B1 publication Critical patent/EP2029602B1/de
Priority to CY20101100682T priority patent/CY1110229T1/el
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a class of triazolopyrazine compounds capable of binding to the active site of a serine/threonine kinase, the expression of which is involved in the pathway resulting in the degradation of extra-cellular matrix (ECM), joint degeneration and diseases involving such degradation and/or inflammation.
  • ECM extra-cellular matrix
  • Diseases involving the degradation of extra-cellular matrix include, but are not limited to, psoriatic arthritis, juvenile arthritis, early arthritis, reactive arthritis, osteoarthritis, ankylosing spondylitis, osteoporosis, muskulo skeletal diseases like tendonitis and periodontal disease, cancer metastasis, airway diseases (COPD, asthma), renal and liver fibrosis, cardio-vascular diseases like atherosclerosis and heart failure, and neurological diseases like neuroinflammation and multiple sclerosis.
  • Diseases involving primarily joint degeneration include, but are not limited to, psoriatic arthritis, juvenile arthritis, early arthritis, reactive arthritis, osteoarthritis, and ankylosing spondylitis.
  • Rheumatoid arthritis is a chronic joint degenerative disease, characterized by inflammation and destruction of the joint structures. When the disease is unchecked, it leads to substantial disability and pain due to loss of joint functionality and even premature death. The aim of an RA therapy, therefore, is not to slow down the disease but to attain remission in order to stop the joint destruction. Besides the severity of the disease outcome, the high prevalence of RA ( ⁇ 0.8% of adults are affected worldwide) means a high socio-economic impact. (For reviews on RA, we refer to Smolen and Steiner (2003); Lee and Weinblatt (2001); Choy and Panayi (2001); O'Dell (2004) and Firestein (2003)).
  • RA auto-immune disease
  • B-cells, T-cells, macrophages, fibroblasts, endothelial cells, dendritic cells and others B-cells, T-cells, macrophages, fibroblasts, endothelial cells, dendritic cells and others.
  • cytokines an increased production of various cytokines is observed in the joints and tissues surrounding the joint (e.g. TNF- ⁇ , IL-6, IL-I, IL-15, IL-18 and others).
  • the pannus mediates the degradation of the adjacent cartilage, leading to the narrowing of the joint space, and has the potential to invade adjacent bone and cartilage.
  • bone and cartilage tissues are composed mainly of collagen type I or II, respectively, the pannus destructive and invasive properties are mediated by the secretion of collagenolytic proteases, principally the matrix metallo proteinases (MMPs).
  • MMPs matrix metallo proteinases
  • the erosion of the bone under and adjacent to the cartilage is also part of the RA process, and results principally from the presence of osteoclasts at the interface of bone and pannus.
  • Osteoclasts are multinucleated cells that, upon adhesion to the bone tissue, form a closed compartment, within which the osteoclasts secrete proteases (Cathepsin K, MMP9) that degrade the bone tissue.
  • the osteoclast population in the joint is abnormally increased by osteoblast formation from precursor cells induced by the secretion of the receptor activator of NFKB ligand (RANKL) by activated SFs and T-cells.
  • RNKL NFKB ligand
  • Collagenstype I and collagen type II are the main components of bone and cartilage, respectively.
  • Collagen proteins typically organise into multimeric structures referred to as collagen fibrils. Native collagen fibrils are very resistant to proteolytic cleavage.
  • MMPs and Cathepsins are the most sensitive collagen in the body.
  • Cathepsins cathepsin K, which is active mainly in osteoclasts, is the best characterised.
  • MMPs MMPl, MMP2, MMP8 MMP13 and MMP14 are known to have collagenolytic properties.
  • MMPl represents a highly relevant collagen degrading protein.
  • cytokines relevant in the RA pathology e.g. TNF- ⁇ and ILlB
  • MMPl expression by SFs therefore is a relevant readout in the field of RA as it is indicative for the activation of SFs towards an erosive phenotype that, in vivo, is responsible for cartilage degradation. Inhibition of the MMPl expression by SFs represents a valuable therapeutic approach towards the treatment of RA.
  • the activity of the ECM-degrading proteins can also be causative or correlate with the progression of various diseases different from RA, e.g. other diseases that involve the degradation of the joints. These diseases include, but are not limited to, psoriatic arthritis, juvenile arthritis, early arthritis, reactive arthritis, osteoarthritis, and ankylosing spondylitis.
  • osteoporosis Other diseases that may be treatable with compounds identified according to the present invention and using the targets involved in the expression of MMPs as described herein are osteoporosis, muscular skeletal diseases like tendonitis and periodontal disease (Gapski et al., 2004), cancer metastasis (Coussens et al., 2002), airway diseases (COPD, asthma) (Suzuki et al., 2004), lung, renal fibrosis (Schanstra et al., 2002), liver fibrosis associated with chronic hepatitis C (Reiff et al., 2005), cardio-vascular diseases like atherosclerosis and heart failure (Creemers et al., 2001), and neurological diseases like neuroinflammation and multiple sclerosis (Rosenberg, 2002). Patients suffering from such diseases may benefit from stabilizing the ECM (by protecting it from degradation).
  • MAPKAPK5 Kinase- Activated Protein Kinase 5
  • PRAK Nuclear Localization signal
  • NES nuclear export signal
  • Endogenous MAPKAPK5 is predominantly present in the cytoplasm, but stress or cytokine activation of the cells mediates its translocation into the nucleus (New et al., 2003). This event is dependent on phosphorylation of MAPKAPK5.
  • Thrl82 is the regulatory phosphorylation site of MAPKAPK5.
  • MAPKAPK5 knock-out mice have been generated that are viable and fertile. The phenotype of these mice is quite different from that of mice deficient for MAPKAPK2, a MAPKAPK5 related kinase that is regulated by p38 ⁇ (Shi et al., 2003). This indicates that the function of each protein is distinct and that neither kinase can compensate for the other's activity. Taken together, MAPKAPK5 and MAPKAPK2 represent distinct targets with a non-redundant role.
  • MAPK6 also referred to as ERK3
  • NSAIDS Non-steroidal anti-inflammatory drugs
  • RA RA-associated joint destruction
  • Corticosteroids were found to decrease the progression of RA as detected radiographically and are used at low doses to treat part of the RA patients (30 to 60%). Serious side effects, however, are associated with long corticosteroid use (skin thinning, osteoporosis, cataracts, hypertension, hyperlipidemia).
  • Synthetic DMARDs Disease-Modifying Anti-Rheumatic Drugs
  • DMARDs Disease-Modifying Anti-Rheumatic Drugs
  • these drugs only have a limited efficacy (joint destruction is only slowed down but not blocked by DMARDs such that disease progression in the long term continues).
  • the lack of efficacy is indicated by the fact that, on average, only 30% of the patients achieve an ACR40 score after 24 months treatment with methotrexate. This means that, according to the American College of Rheumatology, only 30% of the patients achieve a 50% improvement of their symptoms (O'Dell et al., 1996).
  • Biological DMARDs are therapeutic proteins that inactivate cytokines (e.g. TNF- ⁇ ) or cells (e.g. T-cells or B-cells) that have an important role in the RA pathophysiology (Kremer et al., 2003; Edwards et al., 2004).
  • TNF- ⁇ -blockers Infliximab, Etanercept, Adalimumab
  • methotrexate combination therapy is the most effective RA treatment currently available, it is striking that even this therapy only achieves a 50% improvement (ACR40) in disease symptoms in 50-60% of patients after 12 months therapy (St Clair et al., 2004).
  • the TNF- ⁇ blockers also share the general disadvantages of the biological class of therapeutics, which are the unpleasant way of administration (frequent injections accompanied by infusion site reactions) and the high production cost.
  • Newer agents in late development phase target T-cell co-stimulatory molecules and B-cells.
  • the efficacy of these agents is expected to be similar to that of the TNF- ⁇ blockers.
  • the present invention is based on the discovery of that MAPKAPK5 functions in the pathway that results in the expression of MMPl, and that inhibitors of MAPKAPK5 activity, such as the compounds of the present invention, are useful for the treatment of diseases involving the abnormally high expression of MMP activity.
  • the present invention relates to compounds having matrix metallo proteinase inhibiting properties in a mammalian cell, according to formula (I): wherein:
  • E is NH or CR"R6, when k is zero, and is NH or CR"R6a, when k is one;
  • F is sulphur, oxygen or NH
  • T is oxygen or NR
  • U, V, W and X are independently CR"R7 or NR"; Y is CR" or N;
  • Z is hydrogen, amino, hydroxyl, lower alkoxy, carbamoyl, carboxyl, SO 2 RZ, SO 2 NRRZ, -
  • R is independently hydrogen or lower alkyl
  • R" is H or forms a double bond with an adjacent atom
  • Rl is H; R2; or lower alkyl, lower cycloalkyl and lower alkyl-lower cycloalkyl, optionally substituted with one or more R2;
  • R3 is H or forms a double bond with an adjacent R";
  • R2 is H, F, Cl; CN; COOR4; 0R4; C(O)N(R4R5); S(O) 2 N(R4R5); lower alkyl; O- lower alkyl;
  • R6 is hydrogen, amino, hydroxyl, carbamoyl, carboxyl, SO 2 R, NRR', -(CO)-OR, or -(CO)-NRR';
  • R6a is R6, Cl, F, lower alkoxy, cyano, trifluoromethoxy; or together with the adjacent be -
  • R7 is independently hydrogen, halogen, lower alkyl or lower alkoxy;
  • Rz is hydrogen, lower alkyl, lower alkanoyl, phenyl, 1-loweralkyl pyrrolidin-3-yl, pyrazol-4-yl, pyrazol-2-yl, or lower alkyl, lower alkanoyl, phenyl, 1-loweralkyl pyrrolidin-3-yl, pyrazol-4- yl, pyrazol-2-yl or pyrid-3-yl substituted by one or more of hydroxyl, amino, mono- or di- loweralkylamino, acetamidyl, lower alkanoyl, lower alkyl, 4-hydroxy-phenyl, 3- aminomethylphenyl, lower alkyl sulfonyl, 4-diloweralkylaminophenyl, pyrid-3-yl, lH-indol-
  • R and Rz together may be -(CHR) q -T-(CHR) r - and form a five or six member heterocyclic ring with the nitrogen to which they are bonded;
  • Rz and R7 together may be -(CHR") n -NR-(CHR") p -, and form a five or six member heterocyclic ring fused to the ring to which they are bonded;
  • b and d are independently O or 1; provided at least one of b or d is 1; k is O or 1 ; m is O or 1 ; n and p are independently O, 1 or 2; q and r are 1 or 2; x is o or 1 ; with the provisos that at least one of R7 or Rz is other than hydrogen; or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.
  • Another aspect of the present invention is compounds according to formula III:
  • R 1 is H, or substituted or unsubstituted alkyl; and each of R 8 and R 9 is independently selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers, isotopic variants and tautomers thereof.
  • R 8 is selected from substituted or unsubstituted cyclopentyl, cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidine, and substituted or unsubstituted pyrazine, substituted or unsubstituted pyrrole, substituted or unsubstituted pyrazole and substituted or unsubstituted imidazole.
  • R 1 is H, Me, Et, i-Pr or
  • R 1 is H.
  • Another aspect of the present invention relates to compounds according to formula
  • IVa, IVb, IVc, or IVd
  • L is a bond, -CO-, -O(CH 2 ) ml -, -CON(H)(CH 2 ) ml -, or - NHCO-; the subscript ml is selected from 1-4; the ring P is substituted or unsubstituted heterocycloalkyl; the subscript n is selected from 1-4; each R 8a is independently selected from hydrogen, substituted or unsubstituted alkyl, alkoxy, cyano, carbamoyl, CHO, and halo; and R 9 is independently selected from substituted or unsubstituted aryl and heteroaryl; or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers, isotopic variants and tautomers thereof.
  • R 9 is substituted or unsubstituted aryl. In another embodiment, R 9 is substituted or unsubstituted phenyl. [0024] In a one embodiment, with respect to compounds of formulae IH-IVd, R 9 is substituted or unsubstituted heteroaryl. In another embodiment, R 9 is substituted or unsubstituted pyridyl.
  • R 9 is selected from substituted or unsubstituted phenyl, indolyl, isoinolyl, pyrrolyl, furanyl, thienyl, pyrazolyl, oxazolyl, and thiazolyl.
  • the present invention provides pharmaceutical compositions comprising a triazolopyrazine compound of the invention, and a pharmaceutical carrier, excipient or diluent.
  • the pharmaceutical composition can comprise one or more of the compounds described herein.
  • the compounds of the present invention useful in the pharmaceutical compositions and treatment methods disclosed herein are all pharmaceutically acceptable as prepared and used.
  • Another aspect of this invention relates to the use of the present compound in a therapeutic method, a pharmaceutical composition, and the manufacture of such composition, useful for the treatment of diseases involving inflammation, collagen degradation, and in particular, diseases characteristic of abnormal matrix metallo protease (MMPl) and/or Mitogen- Activated Protein-Kinase
  • MMPl abnormal matrix metallo protease
  • MAPKAPK5 Activated Protein Kinase 5
  • RA rheumatoid arthritis
  • This invention also relates to processes for the preparation of the present compounds.
  • Figure 1 This diagram shows the striking histological differences between a healthy joint and that of a RA patient.
  • FIG. 1 This chart shows the increased expression of MMPl in synovial fibroblasts triggered with cytokines involved in rheumatoid arthritis pathology.
  • FIG. 3 shows the dose-dependent inhibition of the "TNF- ⁇ -based trigger"-induced expression of MMPl by SFs by a known anti- inflammatory compound.
  • Figure 4. This gel shows the reduction, at the protein level, of the expression of
  • MAPKAPK5 in SFs by infection of the cells with Ad-siRNA virus targeting MAPKAPK5.
  • halo such as fluoro, chloro, bromo
  • -CN -CF 3
  • -OH -OCF 3
  • C 2 -C 6 alkenyl C 3 -C 6 alkynyl
  • CpC 6 alkoxy aryl and di-C r C 6 alkylamino.
  • Alkoxy means alkyl-O-. Exemplary alkoxy includes methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, and heptoxy. Preferred alkoxy groups are lower alkoxy.
  • Alkyl means straight or branched aliphatic hydrocarbon having 1 to about 20 carbon atoms. Preferred alkyl has 1 to about 12 carbon atoms. More preferred is lower alkyl. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl is attached to a linear alkyl chain.
  • alkyl amino means alkyl-NH-.
  • Preferred alkyl amino is (Ci-Ce)-alkyl amino.
  • Exemplary alkyl amino includes methylamino and ethylamino.
  • amino lower alkanoyl means NH 2 -R-CO-, where R is lower alkylene.
  • Preferred groups include aminoethanoyl and aminoacetyl.
  • Carbamoyl lower alkyl means the radical NH 2 CO-lower alkyl-. Preferred groups include carbamoylethyl and carbamoylmethyl.
  • Carboxy lower alkyl ester means a lower alkyl ester of a carboxy radical, -COO- group.
  • Halo or "halogen” means fluoro, chloro, bromo, or iodo.
  • Haldrogen means in the context of a substituent that -H is present at the compound position and also includes its isotope, deuterium.
  • “Lower alkanoyl amino” means an amino group with an organic functional group R-
  • “Lower alkyl” means 1 to about 6 carbon atoms in a linear alkyl chain that may be straight or branched.
  • “Lower alkoxy” means 1 to about 6 carbon atoms in a linear alkyl chain that may be straight or branched, and that is bonded by an oxygen atom.
  • “Lower alkyl sulphonamide” refers to a lower alkyl amide of sulphonamide of the formula -SO 2 NR 515 R*, where R* is hydrogen or lower alkyl, and at least one R* is lower alkyl.
  • “Prophylaxis” means a measure taken for the prevention of a disease.
  • Solvate means a physical association of a compound useful in this invention with one or more solvent molecules. This physical association includes hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate” encompasses both solution-phase and isolable solvates.
  • the compounds of the invention may be prepared e.g. in crystalline form and may be solvated or hydrated. Suitable solvates include pharmaceutically acceptable solvates, such as hydrates, and further include both stoichiometric solvates and non-stoichiometric solvates. Conventional solvents include water, ethanol, acetic acid and the like, therefore, representative solvates include hydrates, ethanolates and methanolates.
  • Substituted means that one atom or group of atoms in a molecule is replaced by another atom or group.
  • Sulphonamide refers to a group of compounds containing the chemical group -
  • “Therapeutically effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a subject that is being sought by a medical doctor or other clinician.
  • the “therapeutically effective amount” can vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.
  • the term "effective matrix metallo-protease inhibiting amount” is intended to mean that effective amount of an compound of the present invention that will bring about a biologically meaningful decrease in the production of MMP-I in the subject's disease affected tissues such that extracellular matrix degradation is meaningfully reduced.
  • a compound having matrix metallo-protease inhibiting properties or a "matrix metallo-protease inhibiting compound” means a compound of the present invention that provided to a cell in effective amounts is able to cause a biologically meaningful decrease in the production of MMP-I in such cells.
  • Aryl refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system.
  • Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, ⁇ s-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, ple
  • Substituted Aryl includes those groups recited in the definition of "substituted” herein, and particularly refers to an aryl group that may optionally be substituted with 1 or more substituents, for instance from 1 to 5 substituents, particularly 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkenyl, substituted alkenyl, alkoxy, substituted alkoxy, alkoxycarbonyl, alkyl, substituted alkyl, alkynyl, substituted alkynyl, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thiol, alkyl-
  • Bicycloaryl refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent bicycloaromatic ring system.
  • Typical bicycloaryl groups include, but are not limited to, groups derived from indane, indene, naphthalene, tetrahydronaphthalene, and the like. Particularly, an aryl group comprises from 8 to 11 carbon atoms.
  • Bicycloheteroaryl refers to a monovalent bicycloheteroaromatic group derived by the removal of one hydrogen atom from a single atom of a parent bicycloheteroaromatic ring system.
  • Typical bicycloheteroaryl groups include, but are not limited to, groups derived from benzofuran, benzimidazole, benzindazole, benzdioxane, chromene, chromane, cinnoline, phthalazine, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, benzothiazole, benzoxazole, naphthyridine, benzoxadiazole, pteridine, purine, benzopyran, benzpyrazine, pyridopyrimidine, quinazoline, quinoline, quinolizine, quinoxaline, benzomorphan, tetrahydroisoquinoline, tetrahydroquinoline, and the like.
  • the bicycloheteroaryl group is between 9-11 membered bicycloheteroaryl, with 5-10 membered heteroaryl being particularly preferred.
  • Particular bicycloheteroaryl groups are those derived from benzothiophene, benzofuran, benzothiazole, indole, quinoline, isoquinoline, benzimidazole, benzoxazole and benzdioxane.
  • Carbamoyl refers to the radical -C(O)N(R 42 ) 2 where each R 42 group is independently hydrogen, alkyl, cycloalkyl or aryl, as defined herein, which may be optionally substituted as defined herein.
  • Carbamoyl refers to -C(O)-NH 2 .
  • Cycloalkyl refers to cyclic hydrocarbyl groups having from 3 to about 10 carbon atoms and having a single cyclic ring or multiple condensed rings, including fused and bridged ring systems, which optionally can be substituted with from 1 to 3 alkyl groups.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, 1 -methylcyclopropyl, 2-methylcyclopentyl, 2-methylcyclooctyl, and the like, and multiple ring structures such as adamantanyl, and the like.
  • Substituted cycloalkyl includes those groups recited in the definition of
  • substituted herein, and particularly refers to a cycloalkyl group having 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O) 2 - and aryl-S(O) 2 -.
  • substituents for instance
  • Substituted refers to a group in which one or more hydrogen atoms are each independently replaced with the same or different substituent(s).
  • R 52 and R 53 may be hydrogen and at least one of R 52 and R 53 is each independently selected from alkyl, alkenyl, alkynyl, cycloheteroalkyl, alkanoyl, alkoxy, aryloxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 54 COR 55 , NR 54 SOR 55 ; NR 54 SO 2 R 57 , COOalkyl, COOaryl, CONR 54 R 55 , CONR 54 OR 55 , NR 54 R 55 , SO 2 NR 54 R 55 , S-alkyl, S-alkyl, SOalkyl, S0 2 alkyl, Saryl, SOaryl, S0 2 aryl; or R 52 and R 53 may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O or S
  • R 54 , R 55 , and R 56 are independently hydrogen, alkyl, alkenyl, alkynyl, perfluoroalkyl, cycloalkyl, cycloheteroalkyl, aryl, substituted aryl, heteroaryl, substituted or hetero alkyl or the like.
  • Hetero when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g. heteroalkyl, cycloalkyl, e.g. cycloheteroalkyl, aryl, e.g. heteroaryl, cycloalkenyl, cycloheteroalkenyl, and the like having from 1 to 5, and especially from 1 to 3 heteroatoms.
  • Heteroaryl refers to a monovalent heteroaromatic group derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring system.
  • Typical heteroaryl groups include, but are not limited to, groups derived from acridine, arsindole, carbazole, ⁇ -carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole,
  • the heteroaryl group is between 5-15 membered heteroaryl, with 5-10 membered heteroaryl being particularly preferred.
  • Particular heteroaryl groups are those derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyrazine.
  • Examples of representative heteroaryls include the following:
  • each Y is selected from carbonyl, N, NR 58 , O, and S; and R 58 is independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, heteroalkyl or the like.
  • cycloheteroalkyl refers to a stable heterocyclic non- aromatic ring and fused rings containing one or more heteroatoms independently selected from N, O and S.
  • a fused heterocyclic ring system may include carbocyclic rings and need only include one heterocyclic ring.
  • heterocyclic rings include, but are not limited to, piperazinyl, homopiperazinyl, piperidinyl and morpholinyl, and are shown in the following illustrative examples:
  • each X is selected from CR 2 , NR , O and S; and each Y is selected from NR , O and S; and R 58 is independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, heteroalkyl or the like.
  • cycloheteroalkyl rings may be optionally substituted with one or more groups selected from the group consisting of acyl, acylamino, acyloxy, alkoxy, substituted alkoxy, alkoxycarbonyl, alkoxycarbonylamino, amino, substituted amino, aminocarbonyl, aminocarbonylamino, aminocarbonyloxy, aryl, aryloxy, azido, carboxyl, cyano, cycloalkyl, substituted cycloalkyl, halogen, hydroxyl, keto, nitro, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioketo, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O) 2 - and aryl-S(O) 2 -.
  • Substituting groups include carbonyl or thiocarbonyl which provide, for example, lactam and urea derivative
  • each X is selected from CR 58 2 , NR 58 , O and S; and each Y is selected from carbonyl, N, NR 58 , O and S; and R 58 is independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, heteroalkyl or the like.
  • Examples of representative aryl having hetero atoms containing substitution include the following:
  • each X is selected from C-R 58 2 , NR 58 , O and S; and each Y is selected from carbonyl, NR 58 , O and S; and R 58 is independently hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, heteroalkyl or the like.
  • heterocyclic ring may have one to four heteroatoms so long as the heteroaromatic ring is chemically feasible and stable.
  • “Pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly in humans.
  • “Pharmaceutically acceptable salt” refers to the non-toxic, inorganic and organic acid addition salts, and base addition salts, of compounds of the present invention, in particular they are pharmaceutically acceptable and possess the desired pharmacological activity of the parent compound. These salts can be prepared in situ during the final isolation and purification of compounds useful in the present invention.
  • Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic acid
  • Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like.
  • pharmaceutically acceptable cation refers to a non toxic, acceptable cationic counter-ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like.
  • “Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.
  • Preventing refers to a reduction in risk of acquiring a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop in a subject that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease).
  • Prodrugs refers to compounds, including derivatives of the compounds of the invention, which have cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.
  • Subject includes humans. The terms “human,” “patient” and “subject” are used interchangeably herein..
  • Treating” or “treatment” of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment “treating” or “treatment” refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, “treating” or “treatment” refers to modulating the disease or disorder, either physically, ⁇ e.g., stabilization of a discernible symptom), physiologically, ⁇ e.g., stabilization of a physical parameter), or both. In yet another embodiment, “treating” or “treatment” refers to delaying the onset of the disease or disorder.
  • Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides.
  • Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are preferred prodrugs.
  • double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • Preferred are the Ci to Cg alkyl, C 2 -C8 alkenyl, aryl, C 7 -C 12 substituted aryl, and C 7 -Ci 2 arylalkyl esters of the compounds of the invention.
  • the term "isotopic variant” refers to a compound that contains unnatural proportions of isotopes at one or more of the atoms that constitute such compound.
  • an "isotopic variant" of a compound can contain one or more non-radioactive isotopes, such as for example, deuterium ( 2 H or D), carbon-13 ( 13 C), nitrogen-15 ( 15 N), or the like.
  • non-radioactive isotopes such as for example, deuterium ( 2 H or D), carbon-13 ( 13 C), nitrogen-15 ( 15 N), or the like.
  • the following atoms, where present may vary, so that for example, any hydrogen may be 2 HZO, any carbon may be 13 C, or any nitrogen may be 15 N, and that the presence and placement of such atoms may be determined within the skill of the art.
  • the invention may include the preparation of isotopic variants with radioisotopes, in the instance for example, where the resulting compounds may be used for drug and/or substrate tissue distribution studies.
  • radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 14 C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • compounds may be prepared that are substituted with positron emitting isotopes, such as 11 C, 18 F, 15 O and 13 N, and would be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.
  • PET Positron Emission Topography
  • stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”.
  • enantiomers When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible.
  • An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively).
  • a chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".
  • Tautomers refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of ⁇ electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro- forms of phenylnitromethane, that are likewise formed by treatment with acid or base.
  • Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
  • the compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)- stereoisomers or as mixtures thereof.
  • the present invention is based on the discovery of that MAPKAPK5 functions in the pathway that results in the expression of MMPl, and that inhibitors of MAPKAPK5 activity, such as the compounds of the present invention, are useful for the treatment of diseases involving the abnormally high expression of MMP activity.
  • the present invention relates to compounds having matrix metallo proteinase inhibiting properties in a mammalian cell, according to formula (I):
  • a and B are independently CR2R", NR", oxygen or sulphur;
  • AA is CR2 or N
  • E is NH or CR"R6, when k is zero, and is NH or CR"R6a, when k is one;
  • F is sulphur, oxygen or NH
  • T is oxygen or NR
  • U, V, W and X are independently CR"R7 or NR"; Y is CR" or N;
  • Z is hydrogen, amino, hydroxyl, lower alkoxy, carbamoyl, carboxyl, SO 2 RZ, SO 2 NRRZ, -
  • R is independently hydrogen or lower alkyl
  • R" is H or forms a double bond with an adjacent atom
  • Rl is H; R2; or lower alkyl, lower cycloalkyl and lower alkyl-lower cycloalkyl, optionally substituted with one or more R2;
  • R3 is H or forms a double bond with an adjacent R";
  • R2 is H, F, Cl; CN; COOR4; 0R4; C(O)N(R4R5); S(O) 2 N(R4R5); lower alkyl; O- lower alkyl;
  • R6 is hydrogen, amino, hydroxyl, carbamoyl, carboxyl, SO 2 R, NRR', -(CO)-OR, or -(CO)-NRR';
  • R6a is R6, Cl, F, lower alkoxy, cyano, trifluoromethoxy; or together with the adjacent be -
  • R7 is independently hydrogen, halogen, lower alkyl or lower alkoxy;
  • Rz is hydrogen, lower alkyl, lower alkanoyl, phenyl, 1-loweralkyl pyrrolidin-3-yl, pyrazol-4-yl, pyrazol-2-yl, or lower alkyl, lower alkanoyl, phenyl, 1-loweralkyl pyrrolidin-3-yl, pyrazol-4- yl, pyrazol-2-yl or pyrid-3-yl substituted by one or more of hydroxyl, amino, mono- or di- loweralkylamino, acetamidyl, lower alkanoyl, lower alkyl, 4-hydroxy-phenyl, 3- aminomethylphenyl, lower alkyl sulfonyl, 4-diloweralkylaminophenyl, pyrid-3-yl, lH-indol-
  • R and Rz together may be -(CHR) q -T-(CHR) r - and form a five or six member heterocyclic ring with the nitrogen to which they are bonded;
  • Rz and R7 together may be -(CHR") n -NR-(CHR") p -, and form a five or six member heterocyclic ring fused to the ring to which they are bonded;
  • b and d are independently 0 or 1; provided at least one of b or d is 1;
  • k is 0 or 1 ;
  • m is 0 or 1 ;
  • n and p are independently 0, 1 or 2;
  • q and r are 1 or 2;
  • x is o or 1 ; with the provisos that at least one of R7 or Rz is other than hydrogen; or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof.
  • a preferred aspect of the present invention is a subclass of compounds according to formula II,
  • a and B are independently CR2R", NR", oxygen or sulphur;
  • AA is CR2 or N
  • E is NH or CR"R6, when k is zero, and is NH or CR"R6a, when k is one;
  • F is sulphur, oxygen or NH
  • T is oxygen or NR
  • R" is H or forms a double bond with an adjacent atom
  • R is independently hydrogen or lower alkyl
  • Rl is H; R2; or lower alkyl, lower cycloalkyl and lower alkyl-lower cycloalkyl, optionally substituted with one or more R2;
  • R2 is H, F, Cl; CN; COOR4; OR4; C(O)N(R4R5); S(O) 2 N(R4R5); lower alkyl; O- lower alkyl;
  • R4 and R5 are independently H; F, Cl; or lower alkyl, lower cycloalkyl, or lower alkyl-lower cycloalkyl optionally substituted with one or more of F and Cl;
  • R6 is hydrogen, amino, hydroxyl, carbamoyl, carboxyl, SO 2 R, NRR', -(CO)-OR, or -(CO)-NRR';
  • R6a is R6, Cl, F, lower alkoxy, cyano, trifluoromethoxy; or together with the adjacent be - (CHR") n -NR-(CHR") p -, and form a five or six member heterocyclic ring fused to the ring to which they are bonded;
  • R8 is phenyl independently substituted by R a in the ortho-position, by R b in the meta-position, and by R c in the para-position; pyrid-3-yl; pyrid-3-yl substituted by R c in the 5 -position; or cyclohexyl independently substituted by R a in the 2-position, and by Rd in the 4-position;
  • R a is hydrogen, halogen, lower alkyl, trifluoromethyl or lower alkoxy;
  • Rb is hydrogen, trifluoromethyl, lower alkoxy, lower alkyl sulfonamide, carboxyl, -
  • R c is hydrogen, amino, hydroxyl, lower alkoxy, carbamoyl, carboxyl, SO 2 R, SO 2 NR e R f ,
  • Rb and R c can together form a benzdiazole, or indole substituted in the 3 -position by R';
  • Rd is hydroxyl, halogen, amino, lower alkoxy, or NR e R f ;
  • R e and R f are independently hydrogen, 1-loweralkyl pyrrolidin-3-yl, 1 -R-pyrazol-4-yl, lower alkanoyl, phenyl, or lower alkyl optionally substituted by one or more of 4-hydroxy- phenyl, 3-aminomethylphenyl, lower alkyl sulfonyl, 4-diloweralkylaminophenyl, pyrid-3-yl, lH-indol-3-yl, morpholin-4-yl, hydroxyl, amino, mono- or di- loweralkylamino, or by lower alkanoyl; or R' and R" together are -(CHR) n -T- (CHR) n - and form a five or six member heterocyclic ring with the nitrogen to which they are bonded; m is O, 1, or 2; n is 1 or 2; with the proviso that at least one of R a , Rb and R c
  • a particularly preferred embodiment of the present invention relates to compounds according to formula III:
  • R 1 is H, or substituted or unsubstituted alkyl; and each of R 8 and R 9 is independently selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers, isotopic variants and tautomers thereof.
  • R 8 is selected from substituted or unsubstituted cyclopentyl, cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted pyrimidine, and substituted or unsubstituted pyrazine, substituted or unsubstituted pyrrole, substituted or unsubstituted pyrazole and substituted or unsubstituted imidazole.
  • R 1 is H, Me, Et, i-Pr or
  • R 1 is H.
  • R 8 is selected from substituted or unsubstituted cycloalkyl.
  • R 8 is selected from substituted or unsubstituted cyclohexyl or cyclopentyl.
  • R 8 is selected from substituted or unsubstituted heterocycloalkyl.
  • R 8 is selected from substituted or unsubstituted piperidinyl, morpholinyl, or pyrrolidinyl.
  • R 8 is selected from substituted or unsubstituted phenyl, pyridyl or pyrimidine.
  • R 8 is selected from substituted phenyl, substituted pyridyl, and substituted pyrimidine; and the substitution is -L-R 8d ; and wherein L is selected from a bond, alkylene, heteroalkylene, -O-, -N(R 8e )-, -CO-, -CO 2 -, -SO-,
  • R 8d is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted amino, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroarylalkyl and substituted or unsubstituted aminoalkyl; and
  • R 8e is selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted cycloalkyl. [00100] In one embodiment, with respect to compounds of formula III, R 8 is (R 8a )n
  • L, and R are as described in the preceding paragraph; the subscript n is selected from 1-4; and each R 8a is independently selected from hydrogen, substituted or unsubstituted alkyl, alkoxy, cyano, and halo.
  • R 8 is as described above and the subscript n is 1 and R 8a is Me, Et, Pr, iso-Pr, Cl, F, CN, OMe, or CF 3 .
  • R 8a is at 2-(ortho to -L) position.
  • R 8a is 2-Cl, 2-F, 2-Me or 2-
  • R 8 is as described above and
  • L is a bond, -O-, -CO-, -CON(R 8e )-, or -N(R 8e )CO-;
  • R 8d is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroarylalkyl and substituted or unsubstituted aminoalkyl; and
  • R 8e is selected from H, substituted or unsubstituted alkyl.
  • R 8 is as described above and
  • L is a bond, -O-, -CO-, -CON(R 8e )-, or -N(R 8e )CO-;
  • R 8d is selected from H, alkylaminoethyl, dialkylaminoethyl, cycloalkyl, heterocycloalkyl, arylalkyl, and heteroarylalkyl.
  • R 8 is as described above and
  • L is a bond, -O-, -CO-, -CON(R 8e )-, or -N(R 8e )CO-;
  • R 8d is selected from methylaminoethyl, ethylaminoethyl, dimethylaminoethyl, diethylaminoethyl, substituted or unsubstituted pyrrolidinyl, benzyl and pyridylmethyl.
  • R 8 is as described above and
  • L is a bond, -CO-, SO 2 , -(CH 2 ) ml -, -O(CH 2 ) ml -, -NH(CH 2 ) ml -, -CON(H)(CH 2 ) ml -, or - SO 2 NH(CH 2 ) mr ; the subscript ml is selected from 1-4; and R 8d is
  • L is a bond, -CO-, -O(CH 2 ) ml -, -CON(H)(CH 2 ) ml -, or - NHCO-;
  • R 8 is as described above; L is a bond; and the ring P is substituted or unsubstituted heterocycloalkyl.
  • R 8 is as described above; L is a bond; and the ring P is substituted or unsubstituted piperidine, substituted or unsubstituted piperazine, and substituted or unsubstituted piperidine, morpholine.
  • R 8 is as described above; L is CO; and the ring P is substituted or unsubstituted heterocycloalkyl.
  • R 8 is as described above; L is CO; and the ring P is substituted or unsubstituted piperidine, substituted or unsubstituted piperazine, and substituted or unsubstituted piperidine, morpholine.
  • R 8 is as described above; L is -(CH 2 ) m r, -O(CH 2 ) m r, or -NH(CH 2 ) m r; the subscript ml is selected from 1-4; and the ring P is substituted or unsubstituted heterocycloalkyl.
  • R 8 is as described above; L is -(CH 2 ) m r, -O(CH 2 ) m r, or -NH(CH 2 ) m r; the subscript ml is 2 or 3; and the ring P is substituted or unsubstituted piperidine, substituted or unsubstituted piperazine, and substituted or unsubstituted piperidine, morpholine.
  • R 8 is as described above; L is -CON(H)(CH 2 ) mr , or -NHCO(CH 2 ) mr ; the subscript ml is selected from 1-4; and the ring P is substituted or unsubstituted heterocycloalkyl.
  • R 8 is as described above; L is -CON(H)(CH 2 ) m r; the subscript ml is 2 or 3; and the ring P is substituted or unsubstituted piperidine, substituted or unsubstituted piperazine, and substituted or unsubstituted piperidine, morpholine.
  • the compound is according to formula IVa, IVb, IVc, or IVd:
  • L and the ring P are as described above; the subscript n, is selected from 1-4; each R > 8a a i ⁇ s independently selected from hydrogen, substituted or unsubstituted alkyl, alkoxy, cyano, and halo; and R 9 is independently selected from substituted or unsubstituted aryl and heteroaryl; or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers, isotopic variants and tautomers thereof.
  • L is a bond
  • L is methylene, ethylene, propylene, and butylene.
  • L is -CO-.
  • L is -SO 2 -.
  • L is -CON(H)-
  • L is -OCH 2 -
  • L is a bond
  • the ring P is substituted or unsubstituted piperidine, morpholine or piperazine.
  • L and the ring P are as described above; the subscript n is 1 and R 8a is Me, Et, Pr, iso-Pr, Cl, F, CN, OMe, or CF 3 .
  • R 8a is at 2-(ortho to -L) position.
  • R 8a is 2-Cl, 2-F, 2-
  • R 8 is
  • ring P is substituted or unsubstituted heterocycloalkyl; the subscript n is selected from
  • each R 8a is independently selected from hydrogen, substituted or unsubstituted alkyl, alkoxy, cyano, and halo.
  • R 8 is as described above and the ring P is substituted or unsubstituted piperidine, morpholine or piperazine.
  • R 8 is as described above and the subscript n is 4 and each R 8a is H.
  • R 8 is as described above and the subscript n is 1 and R 8a is Me, Et, Pr, iso-Pr, Cl, F, CN, OMe, or CF 3 .
  • R 8a is at the 2-(ortho to N-ring P) position.
  • R 8a is 2-Cl, 2-F, 2-Me or 2-CF 3 .
  • each R 8a is independently selected from hydrogen, substituted or unsubstituted alkyl, alkoxy, cyano, and halo;
  • R 8b is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl;
  • R 8c is hydrogen, substituted or unsubstituted alkyl and the subscript x is selected from 1-8.
  • each R 8a is independently selected from hydrogen, substituted or unsubstituted alkyl, alkoxy, cyano, and halo;
  • R 8b is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl;
  • R c is hydrogen or
  • each R 8a is independently selected from hydrogen, substituted or unsubstituted alkyl, alkoxy, cyano, and halo.
  • each R 8a is independently selected from hydrogen, substituted or unsubstituted alkyl, alkoxy, cyano, and halo; and R 8b is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl.
  • R 8 is as described above and the subscript n is 4 and each R 8a is H.
  • R 8 is as described above and the subscript n is 1 and R 8a is Me, Et, Pr, iso-Pr, Cl, F, CN, OMe, or CF 3 .
  • R 8a is at 2-(ortho to N-ringP) position.
  • R 8a is 2-Cl, 2-F, 2-Me or 2-CF 3 ..
  • R 8 is as described above and R 8b is H.
  • R 8 is as described above and R 8b is substituted or unsubstiuted alkyl.
  • R 8 is as described above and R 8b is substituted or unsubstituted cycloalkyl.
  • R 8 is as described above and R 8b is Me, Et, Pr, i-Pr, t-Bu, i-Bu, CH 2 CF 3 , CF 3 , CH 2 CONH 2 , cyclopropyl or cyclopropylmethyl.
  • R 8 is as described above and R 8b is i-Pr.
  • R 8a is independently selected from hydrogen, substituted or unsubstituted alkyl, alkoxy, cyano, carbamoyl,
  • R 8a is H, Me, F, or Cl. In a preferred embodiment R 8a is H.
  • the compound is according to formula Va, Vb, Vc, Vd, Ve, or Vf: Va Vb Vc
  • R 9 is as described for formula III and R 8b is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl.
  • R 8b is H.
  • R 8b is substituted or unsubstiuted alkyl.
  • R 8b is substituted or unsubstituted cycloalkyl.
  • R 8b is Me, Et, Pr, i-Pr, t-Bu, i-Bu, CH 2 CF 3 , CF 3 , CH 2 CONH 2 , cyclopropyl or cyclopropylmethyl.
  • R 8b is i-
  • R 9 is substituted or unsubstituted aryl. In another embodiment, R 9 is substituted or unsubstituted phenyl. [00152] In a one embodiment, with respect to compounds of formulae III- Vf, R 9 is substituted or unsubstituted heteroaryl. In another embodiment, R 9 is substituted or unsubstituted pyridyl.
  • R 9 is selected from substituted or unsubstituted phenyl, indolyl, isoinolyl, pyrrolyl, furanyl, thienyl, pyrazolyl, oxazolyl, and thiazolyl. [00154] In one embodiment, with respect to compounds of formulae III- Vf, R 9 is
  • each of A 1 , A 2 and A 3 is independently selected from S, O, N, NR 9a , and CR 9a ; each of R 9a is independently H or substituted or unsubstituted alkyl; and R 9b is CONH 2 , CONHMe, or CN. [00155] In further embodiment, with respect to compounds of formulae III- Vf, R 9 is
  • each R 9d is independently H, substituted or unsubstituted alkyl or halo.
  • R 9 is and wherein the subscript m is selected from 1-3 and each R 9d is independently H, substituted or unsubstituted alkyl or halo.
  • R 9 is as described above; and each R 9d is H.
  • R 9 is as described above; m is 1 or 2 and each R 9d is independently Me, Cl or F.
  • the compound is according to formula Via, VIb, Vic, VId, VIe or VIf:
  • R > 8b i ⁇ s hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl.
  • R 8b is H.
  • R 8b is cycloalkyl
  • R 8b is cyclopropyl.
  • R 8b is substituted or unsubstituted alkyl.
  • the compound is according to formula Vila, VIIb, VIIc, VIIc, VIId, VIIe or VIIf:
  • R 8b is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl.
  • R 8b is H.
  • R 8b is cycloalkyl
  • R 8b is cyclopropyl
  • R 8b is substituted or unsubstituted alkyl.
  • the compound is according to formula Villa, VIIIb, VIIIc, VIIId, VIIIe or VIIIf: Villa VIIIc
  • R 8b is H.
  • R 8b is cycloalkyl
  • R 8b is cyclopropyl
  • R 8b is substituted or unsubstituted alkyl.
  • the compound is according to formula IXa, IXb, IXc, IXd, IXe, or IXf: IXa
  • R > 8b i ⁇ s hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl.
  • R 8b is H.
  • R 8b is cycloalkyl
  • R 8b is cyclopropyl
  • R 8b is substituted or unsubstituted alkyl.
  • the compound is according to formula Xa, Xb, Xc, Xd, Xe, or Xf: Xa
  • R 8b is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl.
  • R 8b is H.
  • R 8b is cycloalkyl
  • R 8b is cyclopropyl
  • R 8b is substituted or unsubstituted alkyl.
  • the compound is according to formula XIa, XIb, XIc, XId, XIe or XIf:
  • XId XIe XIf and R , 8b is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl;
  • R 9e is hydrogen, Me, or CN.
  • R 9e is H.
  • R 9e is Me.
  • R 9e is CN.
  • R 8b is H.
  • R 8b is cycloalkyl.
  • R 8b is cyclopropyl.
  • R 8b is substituted or unsubstituted alkyl.
  • the compound is according to formula XIIa, XIIb, XIIc or XIId:
  • the compound is according to formula XIIIa, XIIIb, XIIIc or XIIId:
  • the compound is according to formula XIVa, XIVb, XIVc or XIVd:
  • the compound is according to formula XVa, XVb, or XIVc:
  • R 8b is H, Me, i-Pr, t-Bu, CH 2 CONH 2 , cyclopropylmethyl, or CH 2 CF 3 .
  • L is a bond. In another particular embodiment, L is -0-CH 2 -CH 2 - .
  • the present invention provides prodrugs and de ⁇ vatives of the compounds according to the formulae above
  • Prodrugs are derivatives of the compounds of the invention, which have metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention, which are pharmaceutically active, in vivo
  • a prodrug may be inactive when administered to a subject but is converted in vivo to an active compound of the invention.
  • “Pharmaceutically acceptable prodrugs” as used herein refers to those prodrugs of the compounds useful in the present invention, which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients with undue toxicity, irritation, allergic response commensurate with a reasonable benefit/risk ratio, and effective for their intended use of the compounds of the invention.
  • the term “prodrug” means a compound that is transformed in vivo to yield an effective compound useful in the present invention or a pharmaceutically acceptable salt, hydrate or solvate thereof. The transformation may occur by various mechanisms, such as through hydrolysis in blood.
  • the compounds bearing metabolically cleavable groups have the advantage that they may exhibit improved bioavailability as a result of enhanced solubility and/or rate of absorption conferred upon the parent compound by virtue of the presence of the metabolically cleavable group, thus, such compounds act as pro-drugs.
  • a thorough discussion is provided in Design of Prodrugs, H. Bundgaard, ed., Elsevier (1985); Methods in Enzymology; K. Widder et al, Ed., Academic Press, 42, 309-396 (1985); A Textbook of Drug Design and Development, Krogsgaard- Larsen and H. Bandaged, ed., Chapter 5; "Design and Applications of Prodrugs” 113-191 (1991); Advanced Drug Delivery Reviews, H.
  • Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like.
  • Prodrugs include acid derivatives well know to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides.
  • Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are preferred prodrugs.
  • double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters.
  • Preferred are the Ci to Cg alkyl, C 2 -Cg alkenyl, aryl, C7-C 12 substituted aryl, and C7-C 12 arylalkyl esters of the compounds of the invention.
  • the compounds of this invention are typically administered in the form of a pharmaceutical composition.
  • Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
  • the compounds of this invention are administered in a pharmaceutically effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound -administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.
  • compositions of this invention can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
  • routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal.
  • the compounds of this invention are preferably formulated as either injectable or oral compositions or as salves, as lotions or as patches all for transdermal administration.
  • compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions.
  • the furansulfonic acid compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form.
  • Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like.
  • Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • Injectable compositions are typically based upon injectable sterile saline or phosphate- buffered saline or other injectable carriers known in the art.
  • the active compound in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.
  • Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s), generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • the active ingredients When formulated as a ointment, the active ingredients will typically be combined with either a paraffmic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in- water cream base.
  • Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or the formulation. All such known transdermal formulations and ingredients are included within the scope of this invention.
  • the compounds of this invention can also be administered by a transdermal device.
  • transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
  • the compounds of this invention can also be administered in sustained release forms or from sustained release drug delivery systems.
  • sustained release materials can be found in Remington's Pharmaceutical Sciences.
  • a compound of the invention is admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio.
  • a minor amount of magnesium stearate is added as a lubricant.
  • the mixture is formed into 240-270 mg tablets (80-90 mg of active amide compound per tablet) in a tablet press.
  • a compound of the invention is admixed as a dry powder with a starch diluent in an approximate 1 :1 weight ratio. The mixture is filled into 250 mg capsules (125 mg of active amide compound per capsule).
  • a compound of the invention (125 mg), sucrose (1.75 g) and xanthan gum (4 mg) are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of microcrystalline cellulose and sodium carboxymethyl cellulose (11 :89, 50 mg) in water.
  • Sodium benzoate (10 mg) flavor, and color are diluted with water and added with stirring. Sufficient water is then added to produce a total volume of 5 mL.
  • a compound of the invention is admixed as a dry powder with a dry gelatin binder in an approximate 1 :2 weight ratio.
  • a minor amount of magnesium stearate is added as a lubricant.
  • the mixture is formed into 450-900 mg tablets (150-300 mg of active amide compound) in a tablet press.
  • a compound of the invention is dissolved or suspended in a buffered sterile saline injectable aqueous medium to a concentration of approximately 5 mg/ml.
  • Stearyl alcohol (250 g) and a white petrolatum (250 g) are melted at about 75°C and then a mixture of a compound of the invention (50 g) methylparaben (0.25 g), propylparaben (0.15 g), sodium lauryl sulfate (10 g), and propylene glycol (120 g) dissolved in water (about 370 g) is added and the resulting mixture is stirred until it congeals.
  • the present compounds are used as therapeutic agents for the treatment of conditions in mammals that are causally related or attributable to aberrant activity of MMPl and / or MAPKAPK5. Accordingly, the compounds and pharmaceutical compositions of this invention find use as therapeutics for preventing and/or treating inflammatory diseases in mammals including humans.
  • this invention provides a method of treating a mammal susceptible to or afflicted with a condition associated with extra-cellular matrix (ECM) degradation, in particular arthritis, and more particularly, rheumatoid arthritis, which method comprises administering an effective amount of one or more of the compounds of the invention or a pharmaceutical composition just described.
  • ECM extra-cellular matrix
  • the invention provides a method of treating a mammal sucepible to or afflicted with a condition associated with an abnormal cellular expression of MMPl, which comprises administering a therapeutically effective amount of a compound of the invention, or a pharmaceutical composition thereof.
  • the present invention provides a method of treatment or prophylaxis of a condition characterized by abnormal matrix metallo proteinase activity, which comprises administering a therapeutically effective matrix metallo proteinase inhibiting amount of one or more of the compounds of the invention, or pharmaceutical composition thereof.
  • this invention provides methods of treating a mammal susceptible to or afflicted with diseases and disorders which are mediated by or result in inflammation such as, for example rheumatoid arthritis and osteoarthritis, myocardial infarction, various autoimmune diseases and disorders, uveitis and atherosclerosis; itch / pruritus such as, for example psoriasis; and renal disorders method comprises administering an effective condition-treating or condition-preventing amount of one or more of the pharmaceutical compositions just described.
  • This invention also relates to the use of the present compounds in the manufacture of a medicament for treatment or prophylaxis of a condition prevented, ameliorated or eliminated by administration of an inhibitor of Mitogen- Activated Protein Kinase- Activated Protein Kinase 5, or a condition characterised by abnormal collagenase activity, or a condition associated with ECM degradation or a condition selected from diseases involving inflammation, most preferably in for the treatment of rheumatoid arthritis.
  • a preferred regimen of the present method comprises the administration to a subject in suffering from a disease condition characterized by inflammatory, with an effective matrix metallo- protease inhibiting amount of a compound of the present invention for a period of time sufficient to reduce the abnormal levels of extracellular matrix degradation in the patient, and preferably terminate, the self-perpetuating processes responsible for said degradation.
  • a special embodiment of the method comprises administering of an effective matrix metallo-protease inhibiting amount of a compound of the present invention to a subject patient suffering from or susceptible to the development of rheumatoid arthritis, for a period of time sufficient to reduce or prevent, respectively, collagen and bone degradation in the joints of said patient, and preferably terminate, the self-perpetuating processes responsible for said degradation.
  • Injection dose levels range from about 0.1 mg/kg/hour to at least 10 mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to 96 hours.
  • a preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels.
  • the maximum total dose is not expected to exceed about 2 g/day for a 40 to 80 kg human patient.
  • each dose provides from about 0.01 to about 20 mg/kg of the compound of the invention, with preferred doses each providing from about 0.1 to about 10 mg/kg and especially about 1 to about 5 mg/kg.
  • Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses.
  • the compounds of this invention When used to prevent the onset of an inflammatory condition, the compounds of this invention will be administered to a patient at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above.
  • Patients at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition.
  • the compounds of this invention can be administered as the sole active agent or they can be administered in combination with other agents, including other compounds that demonstrate the same or a similar therapeutic activity, and that are determined to safe and efficacious for such combined administration.
  • the triazolo[l,5-a]pyridyl compounds of this invention can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given; other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures. [00243] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions.
  • Preparative HPLC Waters XBridge Prep C18 5 ⁇ m ODB 19mm ID x 100mm L (Part No.186002978). All the methods are using MeCN/H2O gradients. H2O contains either 0.1% TFA or 0.1% NH3.
  • Step 3 5,8-Dibromo-[l ,2,4Jtriazolo[l ,5-aJpyrazine
  • N-(3,6-dibromo-pyrazin-2-yl)-jV-hydroxyformamidine (17.4 mg, 58.80 mmol) is treated with polyphosphoric acid (150 g) for one hour at 5O 0 C and then for 1.75 hours at 7O 0 C. After cooling to room temperature, water is added to the reaction mixture. The resultant suspension is brought to pH 8 by careful addition of solid NaHC ⁇ 3 in small portions. The precipitate formed is collected by filtration, washed once with IN NaOH, three times with water and dried in vacuo. The residue is partitioned between ethyl acetate and IN NaOH and the organic phase is washed one more time with IN NaOH and once with brine.
  • Step 4 (5-Bromo-[l,2,4Jtriazolo[l,5-aJpyrazin-8-yl)-(4-morpholin-4-ylphenyl)amine
  • Step 5 (4-Morpholin-4-ylphenyl)-[5-(lH-pyrazol-4-yl)-[l,2,4Jtriazolo[l,5-aJpyrazin-8-ylJamine
  • Step 1 [5-(2-Methoxy-pyridin-4-yl)-[l,2,4Jtriazolo[l,5-aJpyrazin-8-ylJ-[4-(4-methyl-piperazin-l-yl)- phenyl] -amine
  • This compound may be prepared using methods as described for Compound 6, step 4 using (5-bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-yl)-[4-(4-methyl-piperazin-l-yl)-phenyl]-amine
  • Step 2 4-(8-(4-(4-Methylpiperazin-l-yl)phenylamino)-[l,2, 4]triazolo[l, 5a]pyrazin-5-yl)pyridin- 2(lH)-one
  • Step 1 (5-Bromo-[l,2,4Jtriazolo[l,5-aJpyrazin-8-yl)-[4-(4-methyl-piperazin-l-yl)-phenylJ-amine
  • Step 3 4-(4,4,5,5-Tetramethyl-[l,3,2]dioxaborolan-2-yl)-thiophene-2-carboxylic acid amide
  • Step 4 4- ⁇ 8- [4-(4-Methyl-piperazin- 1 -yl)-phenylamino] -[ 1,2,4] triazolo[l,5-a]pyrazin-5-yl ⁇ - thiophene-2-carboxylic acid amide
  • the tube is sealed and the reaction mixture is heated at 9O 0 C overnight. After cooling to room temperature the reaction mixture is partitioned between ethyl acetate and water. The precipitate is collected by filtration and washed with water (Ix) and ether (2x) and dried in vacuo. The crude product is purified by column chromatography (silica gel, DCM/MeOH/NH 3 96:4) yielding the title compound (43 mg) as a yellow solid.
  • Step 2 5-(4,4,5,5-Tetramethyl-[l,3,2Jdioxaborolan-2-yl)-thiophene-2-carboxylic acid amide
  • Step 3 5- ⁇ 8-[4-(4-Methyl-piperazin-l-yl)-phenylamino] -[ 1,2,4] triazolo[l,5-a]pyrazin-5-yl ⁇ - thiophene-2-carboxylic acid amide
  • This compound may be prepared using methods as described for Compound 6, step 4 using 5-bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-yl)-[4-(4-methyl-piperazin-l-yl)-phenyl]-amine
  • This compound may be prepared using methods as described for Compound 6, step 4 using (5-bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-yl)-(4-morpholin-4-yl-phenyl)-amine (0.2g,
  • This compound may be prepared using methods as described for Compound 6, step 4 using (5-bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-yl)-(4-morpholin-4-yl-phenyl)-amine (0.2g,
  • Step 1 5-Methyl-4-(4, 4, 5, 5-tetramethyl-[l , 3, 2]dioxaborolan-2-yl)-lH-pyrazole
  • This compound may be prepared using methods as described for Compound 86, step 2 using 4-bromo-5-methyl-lH-pyrazole (3g, 18.6mmol), bis(pinacolato)diboron (8.52g, 33.5mmol), PdCl 2 dppf (913mg, l.l l ⁇ mmol) and KOAc (5.49mg, 55.9mmol) in dimethylsulfoxide (3OmL).
  • reaction mixture is purified by silica gel column chromatography eluting with 7:3 followed by 1 :1 petroleum ether: ethyl acetate to afford 5-methyl-4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH- pyrazole (3.87g, 100%).
  • Step 2 5-(5-Methyl-lH-pyrazol-4-yl)-N-(4-(4-methylpiperazin-l-yl)phenyl)-[l,2,4]triazolo[l,5- aJpyrazin-8-amine
  • This compound may be prepared using methods as described for Compound 6, step 4 using (5-bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-yl)-[4-(4-methyl-piperazin-l-yl)-phenyl]-amine
  • Step 1 (5-Bromo-[l,2,4Jtriazolo[l,5-aJpyrazin-8-yl)-(3- ⁇ uoro-4-morpholin-4-yl-phenyl)-amine
  • This compound may be prepared using methods as described for Compound 6, step 1 using 5,8-dibromo-[l,2,4]triazolo[l,5-a]pyrazine (0.5g, 1.799mmol), 3-fluoro-4-morpholin-4-yl- phenylamine (0.53g, 2.70mmol), and DIPEA (0.47OmL, 2.70mmol) in 2-propanol (6mL).
  • the reaction mixture is partitioned between 10% citric acid aqueous solution and DCM.
  • the organic phase is separated and washed with water and brine, dried over MgSO 4 , filtered and concentrated under vacuum to afford the title compound (697mg, 98%) which is used in the next step without further purification.
  • Step 2 N-(3-Fluoro-4-morpholinophenyl)-5-(lH-pyrazol-4-yl)-[ 1 ,2,4] triazolo [ 1 ,5-a] pyrazin-8-amine
  • This compound may be prepared using methods as described for Compound 6, step 4, using (5-bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-yl)-(3-fluoro-4-morpholin-4-yl-phenyl)-amine (lOOmg, 0.254mmol), 4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-pyrazole (99mg, 0.51mmol) and Pd(PPh 3 ) 4 (73mg, 0.063mmol) in 1.5M Na 2 CO 3 (1.36mL, 2.03mmol) and dioxane (4mL).
  • Step 1 5-(5-Bromo-[l, 2, 4] triazolo [1, 5-a]pyrazin-8-ylamino)-2-morpholin-4-yl-benzamide
  • This compound may be prepared using methods as described for Compound 6, step 1 using 5,8-dibromo-[l,2,4]triazolo[l,5-a]pyrazine (250mg, 0.90mmol) 5-amino-2-morpholin-4-yl benzamide (299mg, 1.35mmol) and N,N-diisopropylethylamine (0.24mL, 1.35mmol) in 2-propanol (7mL). Trituration with 'PrOH and Et 2 O affords the title compound (273mg, 73%).
  • This compound may be prepared using methods as described for Compound 6, step 4 using 5-(5-bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-ylamino)-2-morpholin-4-yl-benzamide (140mg, 0.33mmol), 4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-pyrazole (130mg, 0.67mmol) and Pd(PPh 3 ) 4 (96mg, 0.083mmol) in 1.5M K 2 CO 3 (aq) (1.93mL) and dioxane (3.44mL).
  • This compound may be prepared using methods as described for Compound 6, step 4, using (5-bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-yl)-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-amine
  • This compound may be prepared using methods as described for Compound 6, step 4, using (5-bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-yl)-[4-(2-morpholin-4-yl-ethoxy)-phenyl]-amine
  • Step 1 l-(Tetrahydro-pyran-2-yl)-lH-pyrazole
  • Step 3 (4-Morpholin-4-yl-phenyl)-[5-(2H-pyrazol-3-yl)-[l,2,4]triazolo[l,5-a]pyrazin-8-yl]-amine
  • This compound may be prepared using methods as described for Compound 6, step 4, using 5-bromo- [l,2,4]triazolo[l,5-a]pyrazin-8-yl)-[4-(morpholin-4-yl)-phenyl]-amine (lOOmg, 0.267mmol), IH- pyrazole-2-boronic acid (60mg, 0.535mmol), Pd(PPh 3 ) 4 (93mg, 0.08mmol) and Na 2 CO 3 (88mg, 0.80mmol) in DMF (2mL). The reaction mixture is placed in a stem-tube and stirred at 100 0 C for 18 hours. After cooling, the mixture is diluted with NaHCO 3 solution and extracted with EtOAc (4x).
  • This compound may be prepared using methods as described for Compound 6, step 4, using 5-bromo-N-(6-(4-isopropylpiperazin-l-yl)pyridin-3-yl)-[l,2,4]triazolo[l,5-a]pyrazin-8-amine (lOOmg, 0.24mmol), 4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-thiophene-2-carboxamide (121mg, 0.48mmol), and Pd(PPh 3 ) 4 (69mg, 0.059mmol) in 1.5M Na 2 CO 3 (1.28mL, 1.92mmol) and dioxane (3.84mL).
  • Step 1 [5-(4-Carbamoyl-furan-2-yl)-[l,2,4]triazolo[l,5-a]pyrazin-8-yl]-(4-morpholin-4-yl-phenyl)- carbamic acid tert-butyl ester
  • This compound may be prepared using methods as described for Compound 35, step 3 using (4-morpholin-4-yl-phenyl)-(5-tributylstannanyl-[l,2,4]triazolo[l,5-a]pyrazin-8-yl)-carbamic acid tert-butyl ester (137mg, 0.199mmol), 5-bromo-furan-3-carboxamide (76mg, 0.4mmol) and Pd(PPh 3 ) 4 (23mg, 0.020mmol) in DMF (ImL).
  • This compound may be prepared using methods as described for Compound 6, step 4 using (5-bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-yl)-(4-morpholin-4-yl-phenyl)-amine (1-Og,
  • This compound may be prepared using methods as described for Compound 6, step 4, using (5-bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-yl)-(4-morpholin-4-yl-phenyl)-amine (78mg, O.l ⁇ mmol), 4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-furan-2-carboxylic acid amide (lOOmg, 0.34mmol), and Pd(PPh 3 ) 4 (60mg, 0.052mmol) in 1.5M Na 2 CO 3 (aq) (1.ImL, 1.68mmol), and dioxane (3mL).
  • Step 1 (5-Bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-yl)-(4-morpholin-4-yl-phenyl)-carbamic acid tert- butyl ester
  • Step 3 (4-Morpholin-4-yl-phenyl)-[5-(l-oxo-l, 2, 3, 4-tetrahydro-isoquinolin-6-yl)-[ 1 , 2, 4]triazolo[l, 5- aJpyrazin-8-ylJ -carbamic acid tert-butyl ester
  • Step 4 6-[8-(4-Morpholin-4-yl-phenylamino)-[ 1 ,2,4] triazolo [ 1 ,5-a] pyrazin-5-yl] -3 ,4-dihydro-2H- isoquinolin-1-one
  • This compound may be prepared using methods as described for Compound 6, step 4 using 5-bromo-N-(6-(4-isopropylpiperazin-l-yl)pyridin-3-yl)-[l,2,4]triazolo[l,5-a]pyrazin-8-amine (0.6g, 1.44mmol), 5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-2,3-dihydro-isoindol-l-one (0.56g, 2.16mmol) and Pd(PPh 3 ) 4 (0.416g, 0.36mmol) in 1.5M Na 2 CO 3 (7.7mL) and dioxane (23mL).
  • Step 1 (2-Morpholin-4-yl-5-nitro-phenyl)-methanol r .OH r / - ⁇ °
  • Step 4 (5-Bromo-[ 1,2,4] triazolo[l,5-a] pyrazin-8-yl)-[3-(tert-butyl-dimethyl-silanyloxymethyl)-4- morpholin-4-yl-phenyl] -amine
  • Step 5 [5-(5-Bromo-[ 1,2, 4] triazolo[l,5-a]pyrazin-8-ylamino)-2-morpholin-4-yl-phenyl] -methanol
  • Step 6 ⁇ 5-[5-(lH-Pyrazol-4-yl)-[ 1 ,2 ,4] triazolo [ 1 ,5-a] pyrazin-8-ylamino] -2- morpholinophenyljmethanol
  • This compound may be prepared using methods as described for Compound 6, step 4 using [5-(5-bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-ylamino)-2-morpholin-4-yl-phenyl]-methanol (85mg, 0.21mmol), 4-(4,4,5,5-tetramethyl-[l,3,2]dioxa-borolan-2-yl)-lH-pyrazole (81mg, 0.42mmol) and Pd(PPh 3 ) 4 (60mg, 0.052mmol) in 1.5M Na 2 CO 3 (1.12mL) and dioxane (2.OmL).
  • reaction mixture is purified by silica gel column chromatography, eluting with 95:3 DCM:NH 3 (7M in MeOH) followed by reverse phase preparative HPLC purification.
  • the title compound is obtained as a pale brown solid (lOmg, 12%).
  • This compound may be prepared using the methods as described for Compound 120, using (5-bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-yl)-(6-morpholin-4-yl-pyridin-3-yl)amine in Step 4.
  • LCMS: Rt 0.80 min (95 %), m/z (ESI) 364 (M+H) + .
  • This compound may be prepared using the methods described for Compound 120, using (5-bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-yl)-[6-(4-[cyclopropylmethyl]piperazin-l-yl)pyridin-3- yl]amine in step 4.
  • LCMS: Rt 0.80 min (95 %), m/z (ESI) 417 (M+H) + .
  • Compound 43 [6-(4-Isopropylpiperazin-l-yl)pyridin-3-yl]-[5-(lH-pyrazol-4-yl)-
  • This compound may be prepared using methods as described for Compound 120, using (5-bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-yl)-[6-(4-isopropylpiperazin-l-yl)pyridin-3-yl]amine in Step 4.
  • LCMS: Rt 0.77 min (95 %), m/z (ESI) 405 (M+H) + .
  • This compound may be prepared using methods as described for Compound 120, using (5-bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-yl)- ⁇ 6-[4-(2,2,2-trifluoroethyl)piperazin-l-yl]-pyridin- 3-yl ⁇ amine in step 4.
  • LCMS: Rt 0.95 min (95 %), m/z (ESI) 445 (M+H) + .
  • This compound may be prepared using methods as described for Compound 120, Step
  • This compound may be prepared using methods as described for Compound 167, using (5-bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-yl)-(6-morpholin-4-yl-pyridin-3-yl)amine in Step 4.
  • LCMS: Rt 0.85 min (95 %), m/z (ESI) 423 (M+H) + .
  • This compound may be prepared using methods as described for Compound 120, using (5-bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-yl)-(4-morpholin-4-ylphenyl)amine and 4,4,5,5- tetramethyl-2-benzo[b]thiophen-3-yl-[l,3,2]dioxaborolane in step 4.
  • LCMS Rt 0.84 min (95 %), m/z (ESI) 402 (M+H) + .
  • This compound may be prepared using methods as described for Compound 120, using (5-bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-yl)-(4-morpholin-4-ylphenyl)amine and 4,4,5,5- tetramethyl-2-thiophen-3-yl-[l,3,2]dioxaborolane in step 4.
  • LCMS Rt 1.19 min (95 %), m/z (ESI) 379 (M+H) + .
  • This compound may be prepared using the methods as described for Compound 50, using (5-bromo[l,2,4]triazolo[l,5-a]pyrazin-8-yl)-[4-(4-isopropylpiperazin-l-yl)-phenyl]amine in the final step.
  • LCMS: rt 1.11 min (95 %), m/z (ESI) 420 (M+H) + .
  • Step 1 3 -Ethyl- lH-pyr azote N-N H
  • Step 3 4-Bromo-5-ethyl-l-(tetrahydro-pyran-2-yl)-lH-pyrazole and 4-Bromo-3 -ethyl- l-(tetrahydro- pyran-2-yl) - lH-pyr azole
  • Step 4 5-Ethyl-l-(tetrahydro-pyran-2-yl)-4-(4, 4, 5, 5-tetramethyl-[l, 3, 2] dioxaborolan-2-yl)-lH- pyrazote and 3-Ethyl-l-(tetrahydro-pyran-2-yl)-4-(4, 4, 5, 5-tetramethyl-fl, 3, 2] dioxaborolan-2-yl)-lH- pyr azote
  • This compound may be prepared using methods as described for Compound 86, step 2 using 4-bromo-5-ethyl-l-(tetrahydro-pyran-2-yl)-lH-pyrazole and 4-bromo-3-ethyl-l-(tetrahydro- pyran-2-yl)-lH-pyrazole (168mg, 0.65mmol), bis(pinacolato)diboron (331mg, 1.3mmol), PdC ⁇ dppf (53mg, 65 ⁇ mol) and KOAc (190mg, 1.95mmol) in dimethylsulfoxide (2mL).
  • the reaction mixture is purified by silica gel column chromatography eluting with 90:10 petroleum ether: ethyl acetate to afford the title compounds ( ⁇ l.lmg, 31%).
  • Step 5 ⁇ 5-[5-Ethyl-l-(tetrahydro-pyran-2-yl)-lH-pyrazol-4-yl]-[l,2,4]triazolo[l,5-a]pyrazin-8-yl ⁇ - (4-morpholin-4-yl-phenyl) -amine and ⁇ 5-[3-Ethyl-l-(tetrahydro-pyran-2-yl)-lH-pyrazol-4-yl]- [l,2,4]triazolo[l,5-a]pyrazin-8-yl ⁇ -(4-morpholin-4-yl-phenyl)-amine
  • This compound may be prepared using methods as described for Compound 6, step 4 using (5-bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-yl)-(4-morpholin-4-yl-phenyl)-amine (0.032g, 0.085mmol), 5-ethyl-l-(tetrahydro-pyran-2-yl)-4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH- pyrazole and 3-ethyl-l-(tetrahydro-pyran-2-yl)-4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH- pyrazole (0.52mg, 0.17mmol), and Pd(PPh 3 ) 4 (0.025mg, 0.021mmol) in 1.5M Na 2 CO 3 (aq) (0.45mL, O. ⁇
  • Step 6 5-(5-Ethyl-lH-pyrazol-4-yl)-N-(4-morpholinophenyl)-[l,2,4]triazolo[l,5-a]pyrazin-8-amine
  • Step 1 l,l-Dioxo-6-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-l,2-dihydro-l ⁇ - benzofdJisothiazol-3-one
  • This compound may be prepared using methods as described for Compound 86, step 2 using 6-bromo-l,l-dioxo-l,2-dihydro-l ⁇ 6 -benzo[d]isothiazol-3-one (0.5, 1.9mmol), bis(pinacolato)diboron (0.53g, 2.1mmol), PdCl 2 dppf (0.047g, 0.058mmol) and KOAc (0.56g, 5.7mmol) in dioxane (1OmL). The solvent is removed in vacuo and the residue is partitioned between DCM and water. The organic layer is washed with sat NaHC ⁇ 3 and 2M HCl, dried over MgSOzi, filtered and evaporated to afford the title compound (990mg, 169%) used in the next step without further purification.
  • Step 2 (4-Morpholin-4-yl-phenyl)-[5-(l, 1, 3-trioxo-2, 3-dihydro-lH-l ⁇ 6 -benzo[d]isothiazol-6-yl)- [l,2,4]triazolo[l,5-a]pyrazin-8-yl]-carbamic acid tert-butyl ester
  • This compound may be prepared using methods as described for Compound 6, step 4 using (5-bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-yl)-(4-morpholin-4-yl-phenyl)-carbamic acid tert-butyl ester (170mg, 0.36mmol), l,l-dioxo-6-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-l,2-dihydro-l ⁇ 6 -benzo[d]isothiazol-3-one (374mg, 0.72mmol) and Pd(PPh 3 ) 4 (lOOmg, 0.082mmol) in 1.5M Na 2 CO 3 (2mL, 3mmol) and dioxane (6mL).
  • Step 3 6-[8-(4-Morpholin-4-yl-phenylamino)-[l ,2,4Jtriazolo[l ,5-aJpyrazin-5-ylJ-l ,1-dioxo-l ,2- dihydro-1 ⁇ 6 -benzo[d]isothiazol-3-one
  • This compound may be prepared using the methods described for Compound 120, using (5-bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-yl)-[6-(4-[cyclopropylmethyl]piperazin-l-yl)pyridin-3- yl]amine in step 4.
  • LCMS: Rt 0.85 min (95 %), m/z (ESI) 476 (M+H) + .
  • This compound may be prepared using the methods as described for Compound 167, using (5-bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-yl)-[6-(4-isopropylpiperazin-l-yl)pyridin-3-yl]amine in Step 4.
  • LCMS: Rt 0.82 min (95 %), m/z (ESI) 464 (M+H) + .
  • This compound may be prepared using the methods as described for Compound 167, using (5-bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-yl)- ⁇ 6-[4-(2,2,2-trifluoroethyl)piperazin-l-yl]-pyridin- 3-yl ⁇ amine in step 4.
  • LCMS: Rt 0.99 min (95 %), m/z (ESI) 504 (M+H) + .
  • This compound may be prepared using methods as described for Compound 58, using
  • This compound may be prepared using methods as described for Compound 46, using
  • This compound may be prepared using methods as described for Compound 46, using
  • This compound may be prepared using the methods described for Compound 120, using (5-bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-yl)-[6-(4-cyclopropylpiperazin-l-yl)pyridin-3- yl]amine in step 4.
  • LCMS: Rt 0.76 min (95 %), m/z (ESI) 403 (M+H) + .
  • This compound may be prepared using methods as described for Compound 73, using ammonia (7 M in MeOH) is used in step 3.
  • LCMS: Rt 1.00 min (95 %), m/z (ESI) 423 (M+H) + .
  • This compound may be prepared using methods as described for Compound 61, using
  • Step 1 l-Trifluoroacetyl-4-(4-nitrophenyl)piperidine
  • Triethlyamine (1.0 mL, 7.3 mmol) and 4-(4-nitrophenyl)piperidine (1.0 g, 4.8 mmol) are stirred in DCM (25 mL) at 0°C under N 2 and trifluoroacetic anhydride (0.81 mL, 5.8 mmol) is added. The mixture is stirred for three days, allowing the temperature to warm to rt. The solution is then diluted with DCM (50 mL) and washed with water (2 x 15 mL), NaHCO 3 (50% sat. aq., 2 x 15 mL) and brine (15 mL). The solvent is dried over MgS ⁇ 4 and evaporated to afford the desired compound (1.46 g, 4.66 mmol).
  • Step 2 l-(2,2,2-Trifluoroethyl)-4-(4-nitrophenyl)piperidine
  • Step 3 4-fl - (2, 2, 2- Trifluoroethyl)piperidin-4-yl]phenylam ine
  • Step 1 (5-Bromo-[ 1, 2,4] triazolo[l,5-a]pyrazin-8-yl)-[4-(2-morpholin-4-yl-ethoxy)-phenyl] -amine
  • This compound may be prepared using the methods as described for Compound 6, step 4, using (5-bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-yl)-[4-(2-morpholin-4-yl-ethoxy)-phenyl]- amine (80mg, 0.19mmol), 5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-2,3-dihydro-isoindol-l- one (74mg, 0.29mmol), and Pd(PPh 3 ) 4 (55mg, 0.047mmol) in 1.5M Na 2 CO 3 (1.02mL, 1.53mmol) and dioxane (3mL).
  • reaction mixture is purified by silica gel column chromatography eluting with DCM and a 97:3 mixture DCM:NH 3 (7M in MeOH). After trituration using diethyl ether, the title compound is isolated as a solid (61.9mg, 69%). Conversion of the material into the mesylate salt, using IM methanesulfonic acid (0.134mL) in MeOH, affords the title compound (57.1mg).
  • Step 1 (5-Bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-yl)-(2-fluoro-4-morpholin-4-yl-phenyl)-amine
  • This compound may be prepared using methods as described for Compound 6, step 1, using 5,8-dibromo-[l,2,4]triazolo[l,5-a]pyrazine (0.105g, 0.89mmol), 2-fluoro-4-morpholin-4-yl- phenylamine (93mg, 0.474mmol), DIPEA (0.123mL, 0.706mmol) and l,4-diazabicyclo[2.2.2]octane (53mg, 0.472mmol) in 2-propanol (2mL).
  • Step 2 N-(2-Fluoro-4-morpholinophenyl)-5-(lH-pyrazol-4-yl)-[l,2,4]triazolo[l,5-a]pyrazin-8-amine
  • This compound may be prepared using methods as described for Compound 6, step 4, using (5-bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-yl)-(2-fluoro-4-morpholin-4-yl-phenyl)-amine (80mg, 0.203mmol), 4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-pyrazole (79mg, 0.406mmol), and Pd(PPh 3 ) 4 (59mg, 0.051mmol) in 1.5N Na 2 CO 3 (1.09mL, 1.62mmol) and dioxane (3.25mL).
  • reaction mixture is purified by silica gel column chromatography eluting with 97:3 DCM:NH 3 (7M in MeOH). The fractions containing the product are combined and evaporated in vacuo to afford a solid which is triturated with diethyl ether and petroleum ether to yield the title compound (29mg, 38%).
  • Compound 70 (4-(8-(4-Morpholinophenylamino)-[l,2,4]triazolo[l,5-a]pyrazin-5-yl)-lH-pyrazol- 5-yl)methanol
  • Step 1 4-Bromo-5-(tert-butyl-dimethyl-silanyloxymethyl)-lH-pyrazole
  • Step 2 4-Bromo-3- (tert-butyl-dimethyl-silanyloxymethyl) -I- (tetrahydro-pyran-2-yl) - lH-pyrazole and 4-Bromo-5- (tert-butyl-dimethyl-silanyloxymethyl) -I- (tetrahydro-pyran-2-yl) - lH-pyr azole
  • Step 3 ⁇ 5- [5- (tert-Butyl-dimethyl-silanyloxymethyl) - 1 -(tetrahydro-pyran-2-yl) - lH-pyrazol-4-yl] - fl,2,4Jtriazolo[l,5-aJpyrazin-8-yl ⁇ -(4-morpholin-4-yl-phenyl)- carbamic acid tert-butyl ester and ⁇ 5- [3- (tert-Butyl-dimethyl-silanyloxymethyl) -I- (tetrahydro-pyran-2-yl) - lH-pyrazol-4-yl] - [l,2,4Jtriazolo[l,5-aJpyrazin-8-yl ⁇ -(4-morpholin-4-yl-phenyl)-carbamic acid tert-butyl ester
  • This compound may be prepared using the methods as described for Compound 35, step 3 using (4-morpholin-4-yl-phenyl)-(5-tributylstannanyl-[l,2,4]triazolo[l,5-a]pyrazin-8-yl)- carbamic acid tert-butyl ester (210mg, 0.30mmol) 4-bromo-3-(tert-butyl-dimethyl-silanyloxymethyl)- 1 -(tetrahydro-pyran-2-yl)- 1 H-pyrazole and 4-bromo-5-(tert-butyl-dimethyl-silanyloxymethyl)- 1 - (tetrahydro-pyran-2-yl)- 1 H-pyrazole (170mg, 0.45mmol) and tetrakis(triphenylphosphine)palladium(0) (35mg, 0.030mmol) in DMF (4mL).
  • Step 4 4-[8-(4-Morpholin-4-yl-phenylamino)-[ 1,2,4] 'triazolofl,5-aj ' pyrazin-5-yl] -thiazole-2- carboxylic acid methylamide
  • Step 1 4-Bromo-2-bromomethyl-benzoic acid methyl ester
  • Step 3 5-(4, 4, 5, 5-Tetramethyl-fl, 3, 2] dioxaborolan-2-yl)-2, 3-dihydro-isoindol-l-one
  • Step 4 l-Isopropyl-4-(5-nitro-pyridin-2-yl)-piperazine
  • Step 6 5-Bromo-8-(6-(4-isopropylpiperazin-l-yl)pyridin-3-yl)-[l,2,4]triazolo[l,5-a]pyrazin-8-amine
  • This compound may be prepared using methods as described for Compound 6, step 1, using 5,8-dibromo-[l,2,4]triazolo[l,5-a]pyrazine (0.188g, 0.68mmol), 6-(4-isopropyl-piperazin-l-yl)- pyridin-3-ylamine (0.18Og, 0.816mmol) and N-ethyldiisopropyl-amine (0.2OmL, 1.02mmol) in 2- propanol (2mL). Purification of the crude material by silica gel column chromatography, using DCM followed by 95:5 DCM:MeOH, affords the title compound as a pale brown solid (260mg, 92%).
  • Step 5 5-(8-(6-(4-Isopropylpiperazin-l-yl)pyridin-3-ylamino)-[ 1,2,4] triazolo[l,5-a] pyrazin-5- yl)isoindolin- 1 -one
  • This compound may be prepared using methods as described for Compound 6, step 4, using 5-bromo-N-(6-(4-isopropylpiperazin-l-yl)pyridin-3-yl)-[l,2,4]triazolo[l,5-a]pyrazin-8-amine (50mg, 0.12mmol), 5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-2,3-dihydro-isoindol-l-one (56mg, 0.216mmol) and Pd(PPh 3 ) 4 (35mg, 0.03mmol) in 1.5M Na 2 CO 3 (0.64mL) and dioxane (2mL).
  • the crude product is purified by silica gel column chromatography eluting with 95:5 DCM:MeOH followed by 90:10 DCM:MeOH.
  • the title compound is obtained after trituration with a 10:1 mixture «-hexane:DCM (19mg, 34%).
  • Step 1 l-Bromo-2-(2-ethoxyvinylsulfanyl)benzene
  • Step 3 BenzofbJthiophene-7-carboxylic acid ethyl ester
  • Step 5 Benzo [b] thiophene-7 -carboxylic acid amide
  • the aqueous layer is then extracted with dichloromethane and the resulting organic layers are combined, washed with brine, dried over Na 2 SC ⁇ and evaporated.
  • the crude material is purified by LC using DCM as the eluent to afford the title compound as a white solid (300 mg, 41%).
  • Step 7 3-(4,4,5,5-Tetramethyl[l,3,2Jdioxaborolan-2-yl)benzo[bJthiophene-7-carboxylic acid amide
  • Step 8 3-[8-(4-Morpholin-4-yl-phenylamino)-[ 1 ,2,4] triazolo [ 1 ,5-a] pyrazin-5-yl] -benzo [b] thiophene- 7-carboxylic acid amide
  • This compound may be prepared using the methods as described for Compound 120,
  • This compound may be prepared using methods as described for Compound 80, using
  • Step 3 Acetic acid 4-(4,4,5,5-tetramethyl-[l,3,2Jdioxaborolan-2-yl)pyridin-2-ylmethyl ester
  • Step 4 Acetic acid 4- ⁇ 8-[4-(4-isopropyl-piperazin-l-yl)-phenylamino]-[l,2,4]triazolo[l,5-a]pyrazin- 5-yl ⁇ -pyridin-2-ylmethyl ester
  • Step 5 (4- ⁇ 8-[4-(4-Isopropylpiperazin-l-yl)phenylamino]-[l,2,4]triazolo[l,5-a]pyrazin-5-yl ⁇ pyridin- 2-yl)methanol
  • Acetic acid 4- ⁇ 8-[4-(4-isopropylpiperazin-l-yl)phenylamino]-[l,2,4]triazolo[l,5- a]pyrazin-5-yl ⁇ pyridin-2-ylmethyl ester is stirred at room temperature overnight in 10 mL of a 1.5 M solution of potassium carbonate in methanol. The pH is then brought to neutral by addition of 10% aqueous citric acid and the mixture is extracted with DCM. Purification by LC using 98/2 DCM/2M NH 3 in MeOH as the eluent provides the title compound as a yellow powder (40.3 mg, 12.5% over 2 steps).
  • This compound may be prepared using the methods as described for Compound 92, using pyrazole-4-boronic acid in step 4.
  • Step 2 4-(4,4,5 ,5-Tetramethyl-[ 1 ,3 ,2] dioxaborolan-2-yl)-furan-2-carboxylic acid amide
  • Step 3 4-(8-(6-(4-Isopropylpiperazin-l-yl)pyridin-3-ylamino)-[l,2,4]triazolo[l,5-a]pyrazin-5- yl)furan-2-carboxamide
  • This compound may be prepared using methods as described for Compound 6, step 4 using 5-bromo-8-(6-(4-isopropylpiperazin-l-yl)pyridin-3-yl)-[l,2,4]triazolo[l,5-a]pyrazin-8-amine (60mg, 0.144mmol), 4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-furan-2-carboxylic acid amide (59mg, 0.26mmol), and Pd(PPh 3 ) 4 (42mg, 0.036mmol) in 1.5M Na 2 CO 3 (0.8mL, 1.15mmol) and dioxane (2mL).
  • Step 1 l-Isopropyl-4-(4-nitro-phenyl)-piperazine
  • Step 2 4-(4-Isopropyl-piperazin-l-yl)-phenylamine NH,
  • Step 3 (5-Bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-yl)-[4-(4-isopropyl-piperazin-l-yl)-phenyl]-amine
  • This compound may be prepared using methods as described for Compound 6, step 1, using 5,8-dibromo-[l,2,4]triazolo[l,5-a]pyrazine (2g, 7.20mmol), 4-(4-isopropyl-piperazin-l-yl)- phenylamine (1.89g, 8.62mmol) and N,N-diisopropylethylamine (1.88mL, 10.8mmol) in 2-propanol (3OmL) are stirred at 95 0 C overnight. The title compound is isolated after trituration with diethyl ether and petroleum ether as a grey solid (2.59g,
  • Step 4 4-(8-(4-(4-Isopropylpiperazin-l-yl)phenylamino)-[l,2,4]triazolo[l,5-a]pyrazin-5-yl)furan-2- carboxamide
  • This compound may be prepared using methods as described for Compound 6, step 4, using 5-bromo-N-(6-(4-isopropylpiperazin-l-yl)pyridin-3-yl)-[l,2,4]triazolo[l,5-a]pyrazin-8-amine (80mg, 0.21mmol), 4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-furan-2-carboxylic acid amide (lOlmg, 0.42mmol), and Pd(PPh 3 ) 4 (62mg, 0.053mmol) in 1.5M Na 2 CO 3 (aq) (1.143mL, 1.71mmol), and dioxane (4mL).
  • This compound may be prepared using the methods as described for Compound 92, using 2-(aminocarbonyl)thiophene-4-boronic acid in step 4.
  • This compound may be prepared using the methods as described for Compound 83, using (5-bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-yl)-[6-(4-isopropylpiperazin-l-yl)pyridin-3-yl]amine in Step 4.
  • LCMS: Rt 0.71 min (95 %), m/z (ESI) 446 (M+H) + .
  • Step 1 l-Isopropyl-4-(4-nitrophenyl)piperidine
  • 2-iodopropane (240 ⁇ L, 2.4 mmol) are stirred in acetonitrile (3 mL) in a sealed tube at 120°C for 45 min. The mixture is cooled and the solvent removed under reduced pressure. The residue is partitioned between DCM (20 mL) and water (5 mL), the layers are separated and the DCM is washed with water (5 mL) and brine (5 mL) and dried over MgSO 4 . Evaporation of the solvent affords the title compound (300 mg) which is used without further purification.
  • Step 3 (5-Bromo-[ 1 ,2,4] triazolo [ 1 ,5-a] pyrazin-8-yl)-[4-(l-isopropylpiperidin-4-yl)phenyl] amine
  • N,N-Diisopropylethylamine 200 ⁇ L, 1.2 mmol is added to a mixture of 4-(l- isopropylpiperidin-4-yl)phenylamine (220 mg, 1.0 mmol) and 5,8-dibromo-[l,2,4]triazolo[l,5- a]pyrazine (280 mg, 1.0 mmol) in 1 PrOH (5 mL) and heated at reflux for 48 h. The mixture is cooled and the solvent evaporated under reduced pressure to afford an orange-brown solid. This is partitioned between DCM (50 mL) and water (20 mL) and the layers are separated.
  • the organic phase is washed with citric acid (10% aq., 3 x 25 mL).
  • the combined washings are extracted with DCM (25 mL) and then made basic by addition of NaHC ⁇ 3 (s).
  • the mixture is extracted with DCM (3 x 25 mL) and the combined extracts dried over MgS ⁇ 4 and evaporated.
  • the crude product was purified by chromatography on silica gel, eluting with 5% - 10% MeOH in DCM to afford the desired compound, contaminated with the starting aniline. This was recrystallised from MeOH to afford the pure title compound (110 mg).
  • This material may be used to prepare 5- ⁇ 8-[4-(l-isopropylpiperidin-4- yl)phenylamino]-[l,2,4]triazolo[l,5-a]pyrazin-5-yl ⁇ -2,3-dihydroisoindol-l-one in a fashion analogous to step 4 as described for Compound 79.
  • Step 1 4-(4-Amino-phenyl)-3-oxo-piperazine-l-carboxylic acid tert-butyl ester
  • Step 2 l-[4-(5-Bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-ylamino)-phenyl]-piperazin-2-one
  • This compound may be prepared using methods as described for Compound 6, step 1, using 5,8-dibromo-[l,2,4]triazolo[l,5-a]pyrazine (0.283g, l.OOmmol), 4-(4-amino-phenyl)-3-oxo- piperazine-1-carboxylic acid tert-butyl ester (0.30Og, l.OOmmol) and N-ethyldiisopropyl-amine (0.2OmL, 1.02mmol) in 2-propanol (ImL).
  • Step 3 l-(4-(5-(lH-Pyrazol-4-yl)-[l,2,4]triazolo[l,5-a]pyrazin-8-ylamino)phenyl)piperazin-2-one
  • This compound may be prepared using methods as described for Compound 1, step 5 using 1 -[4-(5-bromo-[l ,2,4]triazolo[l ,5-a]pyrazin-8-ylamino)-phenyl]-piperazin-2-one (70mg, 0.18mmol) 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (64mg, 0.33mmol), Pd(PPh 3 ) 4 (21mg, l ⁇ mol) and NaO'Bu (70mg, 0.72mmol) in 2mL of 3:1 DMF/water.
  • Step 1 l-tert-Butyl-4-(4-nitro-phenyl)-piperazine
  • Step 3 (5-Bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-yl)-[4-(4-tert-butyl-piperazin-l-yl)-phenyl]-amine
  • This compound may be prepared using methods as described for Compound 6, step 1, using 5,8-dibromo-[l,2,4]triazolo[l,5-a]pyrazine (0.308g, 1.107mmol), 4-(4-tert-butyl-piperazin-l- yl)-phenylamine (0.31Og, 1.33mmol) and N-ethyldiisopropyl-amine (0.289mL, 1.66mmol) in 2- propanol (5mL). The reaction mixture is partitioned between DCM and IN NaOH, the organic layer is separated and washed with water and brine, dried over MgSOzi, filtered and concentrated under vacuum. Trituration of the residue with diethyl ether and petroleum ether affords the title compound (440mg, 92%) as a cream solid. LCMS: Rt 2.25min (96%).
  • Step 4 5- ⁇ 8-[4-(4-tert-Butyl-piperazin-l-yl)-phenylamino]-[ 1,2,4] triazolo[l,5-a]pyrazin-5-yl ⁇ -2,3- dihydro-isoindol-1-one
  • This compound may be prepared using methods as described for Compound 6, step 4,
  • reaction mixture is partitioned between ethyl acetate and brine, the organic layer is separated, dried over MgSO 4 filtered and evaporated in vacuo.
  • the residue is purified by silica gel column chromatography eluting with 98:2 DCM:NH 3 (7M in MeOH) followed by 95:5 DCM:NH 3 (7M in MeOH) to give a solid which is triturated with diethyl ether and petroleum ether to afford the title compound (71mg, 63%).
  • Step 1 3-Oxo-4- ⁇ 4-[5-(l-oxo-2,3-dihydro-lH-isoindol-5-yl)-[l,2,4]triazolo[l,5-a]pyrazin-8- ylamino] -phenyl ⁇ -piperazine-1 -carboxy Hc acid tert-butyl ester
  • This compound may be prepared using methods as described for Compound 6, step 4, using 4-[4-(5-bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-ylamino)-phenyl]-3-oxo-piperazine-l-carboxylic acid tert-butyl ester (115mg, 0.24mmol), 5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-2,3- dihydro-isoindol-1-one (92mg, 0.35mmol), and Pd(PPh 3 ) 4 (83mg, 0.072mmol) in 1.5M Na 2 CO 3 (aq) (1.3mL, 1.92mmol), and dioxane (2.5mL).
  • reaction mixture is diluted with brine then toluene is added and a precipitate is formed and collected by filtration.
  • the resultant solid is dissolved in DCM and filtered through a silica cartridge to afford the title compound as a yellow solid (60mg, 47%).
  • Step 2 5- ⁇ 8-[4-(2-Oxo-piperazin-l-yl)-phenylaminoJ-[l,2,4Jtriazolo[l,5-aJpyrazin-5-yl ⁇ -2,3-dihydro- isoindol-1-one
  • Nitromethane (10 mL, 169 mmol, 8 equiv.) is added cautiously to a suspension of sodium hydride (4.05 g, 169 mmol, 8 equiv.) and MgSO 4 (40 g) in DMSO (100 mL) at rt and the resulting slurry is stirred for 0.25 h.
  • To the resulting yellow slurry is added 4-bromo-2,6- difluorobenzoic acid methyl ester (5.3 g, 21 mmol) and the mixture is stirred at rt for 3 days at which point all the starting material has been consumed.
  • Step 4 7-Fluoro-5-(4, 4, 5, 5-tetramethyl-fl, 3, 2] dioxaborolan-2-yl)-2, 3-dihydroisoindol-l-one
  • Step 5 7-Fluoro-5- ⁇ 8-[4-(4-isopropylpiperazin-l-yl)-phenylamino]-[ 1,2,4] triazolo[l,5-a] pyrazin-5- yl ⁇ -2, 3-dihydroisoindol-l-one
  • This compound may be prepared using methods as described for Compound 91 using the above boronate.
  • LCMS: Rt 0.90 min (95 %), m/z 487 (M+H) + .
  • Step 1 l-[4-(5-Bromo-[ 1 ,2 ,4j 'triazolo [ 1 ,5-aJ pyrazin-8-ylamino) -phenyl] ' -4-isopropyl-piperazin-2-one
  • Step 2 5-(8-(4-(4-Isopropyl-2-oxopiperazin-l-yl)phenylamino)-[ 1,2,4] 'triazolo [1,5-aJ pyrazin-5- yl)isoindolin- 1 -one
  • This compound may be prepared using methods as described for Compound 6, step 4, using l-[4-(5-bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-ylamino)-phenyl]-4-isopropyl-piperazin-2-one (40mg, 0.09mmol), 5-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-2,3-dihydro-isoindol-l-one (37mg, 0.14mmol), and Pd(PPh 3 ) 4 (31mg, 0.027mmol) in 1.5M Na 2 CO 3 (aq) (0.5mL, 0.75mmol), and dioxane (1.2mL).
  • reaction mixture is diluted with brine then toluene is added and a precipitate is formed and collected by filtration.
  • the filtrate is washed with diethyl ether, petroleum ether and MeOH and then purified by silica gel column chromatography. Elution with 99:1 DCM:NH 3 (7M in MeOH) followed by 98:2 and 95:5 DCM:NH 3 (7M in MeOH) affords the title compound as a yellow solid (24mg, 55%).
  • Step 1 5-Bromo-2-(4-methoxybenzyl)-3 , 3 -dimethyl- 2, 3-dihydroisoindol-l-one
  • a suspension of sodium hydride (130 mg, 60% dispersion in mineral oil, 3.2 mmol) and tetra- n butylammonium iodide (243 mg, 0.68 mmol) in THF (20 mL) is stirred at rt and a solution of 5-bromo-2,3-dihydroisoindol-l-one (675 mg, 3.2 mmol) in THF (20 mL) and DMF (4 mL) is added. After 75 min 4-methoxybenzyl bromide (460 ⁇ L, 3.2 mmol) is added and stirring is continued for 4 h.
  • Step 3 5- ⁇ 8-[4-(4-Isopropylpiperazin-l-yl)-phenylamino] -[ 1 ,2 ,4] triazolo [ 1 ,5-a] pyrazin-5-yl ⁇ -3 ,3- dimethyl-2,3-dihydroisoindol-l-one
  • Step 1 4-(5-Bromo-[ 1 ,2,4] ' triazolo [ 1 ,5-a] pyrazin-8-ylamino) -benzoic acid methyl ester
  • This compound may be prepared using methods as described for Compound 6, step 1 using 5,8-dibromo-[l,2,4]triazolo[l,5-a]pyrazine (250mg, 0.90mmol), 4-aminobenzoic methyl ester (163mg, 1.08mmol) and N-ethyldiisopropyl-amine (0.19mL, 1.08mmol) in 2-propanol (2.5mL). The title compound is obtained after trituration with 2-propanol as a brown solid (148mg, 47%).
  • Step 2 4-(5-Bromo-[ 1 ,2 ,4j 'triazolo [ 1 ,5-aJ 'pyrazin-8-ylamino) -benzoic acid
  • Step 3 4-(5-Bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-ylamino)-N-pyridin-3-ylmethyl-benzamide
  • Step 4 4-(5-(lH-Pyrazol-4-yl)-[ 1 ,2 ,4j 'triazolo [ 1 ,5-aJ pyrazin-8-ylamino) -N-(pyridin-3- ylmethyl)benzamide
  • This compound may be prepared using methods as described for Compound 6, step 4 using 4-(5-bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-ylamino)-N-pyridin-3-ylmethyl-benzamide (lOOmg, 0.24mmol), 4-(4,4,5,5-tetramethyl-[l,3,2]dioxaborolan-2-yl)-lH-pyrazole (93mg, 0.48mmol) and Pd(PPh 3 ) 4 (70mg, O.O ⁇ mmol) in 1.5M K 2 CO 3 (aq) (1.4mL) and dioxane (2.5mL).
  • Step 1 4-[5-(2-Methoxy-pyridin-4-yl)-[l,2,4Jtriazolo[l,5-aJpyrazin-8-ylaminoJ-N-pyridin-3-ylmethyl- benzamide
  • This compound may be prepared using methods as described for Compound 6, step 4 using 4-(5-bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-ylamino)-N-pyridin-3-ylmethyl-benzamide (120mg, 0.28mmol), 2-methoxypyridine-4-boronic acid (87mg, 0.57mmol) and Pd(PPh 3 ) 4 (81mg, 0.07mmol) in 1.5M K 2 CO 3 (aq) (1.6mL) and dioxane (2.9mL).
  • Step 2 4-(5-(2-Oxo-l ,2-dihydropyridin-4-yl)-[l ,2,4Jtriazolo[l ,5-aJpyrazin-8-ylamino)-N-(pyridin-3- ylmethyl)benzamide
  • N-pyridin-3-ylmethyl-benzamide (71.5mg, O.l ⁇ mmol) and pyridinium hydrochloride (91mg, 0.79mmol) in water (0.5mL) in a sealed tube is heated at 15O 0 C for 25 minutes. After this time the solvent is removed in vacuo. The residue is chromatographed on silica gel, eluting with DCM followed by 98:2 and 90:10 DCM:NH 3 (7M in MeOH), and the fractions containing the desired product are combined and evaporated. The title compound is isolated as a yellow solid (34.5mg, 49%).
  • Step 3 4-(5-Bromo-fl,2,4Jtriazolofl,5-aJpyrazin-8-ylamino)-2-hydroxy-N-f(6-methyl-pyridin-3- yl)methyl]benzamide
  • Step 4 2-Methoxy-N-(6-methylpyridin-3-yl)methyl-4-[5-(lH-pyrazol-4-yl)-[l,2,4Jtriazolo[l,5- aJpyrazin-8-ylamino] ' -benzamide
  • the tube is sealed, placed in an ultrasonic bath under a flow of nitrogen gas for 30 seconds and then placed into an oil bath at 85°C.
  • the reaction is stirred for 28 hours, adding additional portions of boronic acid (10 mg) and catalyst (2 mg) after 2 h and 18 h.
  • the crude mixture is absorbed onto SiO 2 and purified by column chromatography, eluting with 1 % - 10% MeOH/DCM.
  • the product obtained is redissolved in MeOH/DCM (4:1, 10 mL) and 0.1 MsOH/MeOH (2 eq) is added, the solvents evaporated and the residue taken up in water and lyophillised to afford the title compound as its bis-mesylate salt (38 mg).
  • LCMS Rt 0.92 min (93.9 %) m/z (ESI) 455 (M+H) + .
  • This compound may be prepared using the methods described for Compound 120, using benzylamine in step 1.
  • This compound may be prepared using methods as described for Compound 129 using
  • This compound may be prepared using methods as described for Compound 129, using 4-isopropylpiperazine in step 5.
  • LCMS: Rt 0.84 min (100 %), m/z (ESI) 432 (M+H) + .
  • Step 1 3-(5-Bromo-[ 1 ,2 ,4] triazolo [ 1 ,5-a] pyrazin-8-ylamino)benzoic acid ethyl ester
  • Step 2 3-[(5-Bromo-[l,2,4]triazolo[l,5-a]pyrazin-8-yl)- ⁇ .& ⁇ -butoxycarbonyl-amino]benzoic acid ethyl ester
  • Step 3 3- ⁇ tert-Butoxycarbonyl-[5-(lH-pyrazol-4-yl)-[ 1,2,4] 'triazolofl,5-aj pyrazin-8-yl] - aminojbenzoic acid ethyl ester

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
EP07729660A 2006-05-31 2007-05-30 Triazolopyrazinverbindungen zur behandlung von degenerations- und entzündungskrankheiten Active EP2029602B1 (de)

Priority Applications (4)

Application Number Priority Date Filing Date Title
SI200730288T SI2029602T1 (sl) 2006-05-31 2007-05-30 Triazolopirazinske spojine, uporabne za zdravljenje degenerativnih in vnetnih bolezni
PL07729660T PL2029602T3 (pl) 2006-05-31 2007-05-30 Związki triazolopirazynowe użyteczne do leczenia chorób zwyrodnieniowych i zapalnych
EP07729660A EP2029602B1 (de) 2006-05-31 2007-05-30 Triazolopyrazinverbindungen zur behandlung von degenerations- und entzündungskrankheiten
CY20101100682T CY1110229T1 (el) 2006-05-31 2010-07-21 Ενωσεις τριαζολοπυραζινης χρησιμες για την θεραπεια εκφυλιστικων & φλεγμονωδων ασθενειων

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
US80355206P 2006-05-31 2006-05-31
US93176407P 2007-05-25 2007-05-25
US93184407P 2007-05-25 2007-05-25
US93176307P 2007-05-25 2007-05-25
US93210007P 2007-05-29 2007-05-29
PCT/EP2007/055246 WO2007138072A2 (en) 2006-05-31 2007-05-30 Triazolopyrazine compounds useful for the treatment of degenerative & inflammatory diseases
EP07729660A EP2029602B1 (de) 2006-05-31 2007-05-30 Triazolopyrazinverbindungen zur behandlung von degenerations- und entzündungskrankheiten

Publications (2)

Publication Number Publication Date
EP2029602A2 true EP2029602A2 (de) 2009-03-04
EP2029602B1 EP2029602B1 (de) 2010-04-21

Family

ID=42664734

Family Applications (1)

Application Number Title Priority Date Filing Date
EP07729660A Active EP2029602B1 (de) 2006-05-31 2007-05-30 Triazolopyrazinverbindungen zur behandlung von degenerations- und entzündungskrankheiten

Country Status (3)

Country Link
EP (1) EP2029602B1 (de)
PL (1) PL2029602T3 (de)
SI (1) SI2029602T1 (de)

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2007138072A2 *

Also Published As

Publication number Publication date
EP2029602B1 (de) 2010-04-21
PL2029602T3 (pl) 2010-09-30
SI2029602T1 (sl) 2010-08-31

Similar Documents

Publication Publication Date Title
WO2007138072A2 (en) Triazolopyrazine compounds useful for the treatment of degenerative & inflammatory diseases
EP2027124B1 (de) Imidazolpyrazinverbindungen zur behandlung von degenerations- und entzündungskrankheiten
AU2020202707B2 (en) Heteroaryl pyridone and aza-pyridone compounds as inhibitors of Btk activity
US10053469B2 (en) Pyridone and aza-pyridone compounds and methods of use
JP5841602B2 (ja) ピリジノン／ピラジノン、その作製方法、および使用方法
TWI494314B (zh) ５,７－取代的－咪唑并［１,２－ｃ］嘧啶
IL274938B2 (en) New compounds and their pharmaceutical preparations for the treatment of diseases
WO2008138842A1 (en) Imidazopyrazines and triazolopyrazine for the treatment of joint degenerative and inflammatory diseases
CN118005640A (zh) Gcn2抑制剂及其用途
MXPA06013250A (es) Inhibidores de quinasa como agentes terapeuticos.
WO2008138843A1 (en) Imidazopyridines and triazolopyrimidines useful for the treatment of joint degenerative & inflammatory diseases
JP2013522334A (ja) ピロロピラジンのキナーゼ阻害剤
CA2821712A1 (en) Substituted n-(1h-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxamide compounds as type iii receptor tyrosine kinase inhibitors
EP2307426A1 (de) Zur behandlung degenerativer und entzündlicher krankheiten geeignete kondensierte pyrazinverbindungen
EP2029602B1 (de) Triazolopyrazinverbindungen zur behandlung von degenerations- und entzündungskrankheiten
CN101454326A (zh) 用于治疗变性和炎性疾病的三唑并吡嗪化合物
ES2345066T3 (es) Compuestos de triazolopirazina utiles para el tratamiento de enfermedades degenerativas e inflamatorias.

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20080326

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA HR MK RS

17Q First examination report despatched

Effective date: 20090520

GRAP Despatch of communication of intention to grant a patent

Free format text: ORIGINAL CODE: EPIDOSNIGR1

GRAS Grant fee paid

Free format text: ORIGINAL CODE: EPIDOSNIGR3

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE SI SK TR

AX Request for extension of the european patent

Extension state: AL BA HR MK RS

REG Reference to a national code

Ref country code: GB

Ref legal event code: FG4D

REG Reference to a national code

Ref country code: CH

Ref legal event code: EP

REG Reference to a national code

Ref country code: IE

Ref legal event code: FG4D

REF Corresponds to:

Ref document number: 602007006010

Country of ref document: DE

Date of ref document: 20100602

Kind code of ref document: P

REG Reference to a national code

Ref country code: HR

Ref legal event code: TUEP

Ref document number: P20100378

Country of ref document: HR

REG Reference to a national code

Ref country code: PT

Ref legal event code: SC4A

Free format text: AVAILABILITY OF NATIONAL TRANSLATION

Effective date: 20100630

REG Reference to a national code

Ref country code: RO

Ref legal event code: EPE

REG Reference to a national code

Ref country code: NL

Ref legal event code: T3

REG Reference to a national code

Ref country code: SE

Ref legal event code: TRGR

REG Reference to a national code

Ref country code: DK

Ref legal event code: T3

REG Reference to a national code

Ref country code: HR

Ref legal event code: T1PR

Ref document number: P20100378

Country of ref document: HR

REG Reference to a national code

Ref country code: GR

Ref legal event code: EP

Ref document number: 20100401728

Country of ref document: GR

REG Reference to a national code

Ref country code: ES

Ref legal event code: FG2A

Ref document number: 2345066

Country of ref document: ES

Kind code of ref document: T3

REG Reference to a national code

Ref country code: PL

Ref legal event code: T3

REG Reference to a national code

Ref country code: SK

Ref legal event code: T3

Ref document number: E 7528

Country of ref document: SK

REG Reference to a national code

Ref country code: HU

Ref legal event code: AG4A

Ref document number: E008332

Country of ref document: HU

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT

26N No opposition filed

Effective date: 20110124

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20100530

REG Reference to a national code

Ref country code: HR

Ref legal event code: ODRP

Ref document number: P20100378

Country of ref document: HR

Payment date: 20110521

Year of fee payment: 5

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IS

Payment date: 20110302

Year of fee payment: 5

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: ES

Payment date: 20110617

Year of fee payment: 5

Ref country code: FR

Payment date: 20110523

Year of fee payment: 5

Ref country code: CH

Payment date: 20110512

Year of fee payment: 5

Ref country code: CZ

Payment date: 20110502

Year of fee payment: 5

Ref country code: PT

Payment date: 20110524

Year of fee payment: 5

Ref country code: GR

Payment date: 20110412

Year of fee payment: 5

Ref country code: TR

Payment date: 20110509

Year of fee payment: 5

Ref country code: LT

Payment date: 20110405

Year of fee payment: 5

Ref country code: SE

Payment date: 20110512

Year of fee payment: 5

Ref country code: LV

Payment date: 20110428

Year of fee payment: 5

Ref country code: MC

Payment date: 20110427

Year of fee payment: 5

Ref country code: LU

Payment date: 20110531

Year of fee payment: 5

Ref country code: IE

Payment date: 20110511

Year of fee payment: 5

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BG

Payment date: 20110429

Year of fee payment: 5

Ref country code: FI

Payment date: 20110511

Year of fee payment: 5

Ref country code: EE

Payment date: 20110405

Year of fee payment: 5

Ref country code: BE

Payment date: 20110511

Year of fee payment: 5

Ref country code: DK

Payment date: 20110512

Year of fee payment: 5

Ref country code: GB

Payment date: 20110525

Year of fee payment: 5

Ref country code: SK

Payment date: 20110427

Year of fee payment: 5

Ref country code: NL

Payment date: 20110526

Year of fee payment: 5

Ref country code: PL

Payment date: 20110415

Year of fee payment: 5

Ref country code: HU

Payment date: 20110513

Year of fee payment: 5

Ref country code: SI

Payment date: 20110408

Year of fee payment: 5

Ref country code: RO

Payment date: 20110413

Year of fee payment: 5

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: IT

Payment date: 20110523

Year of fee payment: 5

Ref country code: DE

Payment date: 20110525

Year of fee payment: 5

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CY

Payment date: 20110415

Year of fee payment: 5

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: MT

Payment date: 20110608

Year of fee payment: 5

BERE Be: lapsed

Owner name: GALAPAGOS N.V.

Effective date: 20120531

REG Reference to a national code

Ref country code: NL

Ref legal event code: V1

Effective date: 20121201

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MC

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120531

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

REG Reference to a national code

Ref country code: SE

Ref legal event code: EUG

REG Reference to a national code

Ref country code: DK

Ref legal event code: EBP

REG Reference to a national code

Ref country code: LT

Ref legal event code: MM4D

Effective date: 20120530

GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 20120530

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120530

Ref country code: CY

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120530

Ref country code: IS

Free format text: LAPSE BECAUSE OF FAILURE TO SUBMIT A TRANSLATION OF THE DESCRIPTION OR TO PAY THE FEE WITHIN THE PRESCRIBED TIME-LIMIT

Effective date: 20121201

Ref country code: SK

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120530

Ref country code: LI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120531

Ref country code: CH

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120531

Ref country code: EE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120531

Ref country code: FI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120530

Ref country code: CZ

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120530

Ref country code: HU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120531

REG Reference to a national code

Ref country code: SK

Ref legal event code: MM4A

Ref document number: E 7528

Country of ref document: SK

Effective date: 20120530

REG Reference to a national code

Ref country code: GR

Ref legal event code: ML

Ref document number: 20100401728

Country of ref document: GR

Effective date: 20121204

REG Reference to a national code

Ref country code: EE

Ref legal event code: MM4A

Ref document number: E004562

Country of ref document: EE

Effective date: 20120531

REG Reference to a national code

Ref country code: IE

Ref legal event code: MM4A

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120531

Ref country code: IT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120530

Ref country code: GR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20121204

Ref country code: LV

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120530

Ref country code: PT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20121130

Ref country code: SI

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120531

Ref country code: SE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120531

REG Reference to a national code

Ref country code: SI

Ref legal event code: KO00

Effective date: 20130104

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

Effective date: 20130131

REG Reference to a national code

Ref country code: DE

Ref legal event code: R119

Ref document number: 602007006010

Country of ref document: DE

Effective date: 20121201

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20121201

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DK

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120531

Ref country code: IE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120530

Ref country code: GB

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120530

Ref country code: FR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120531

REG Reference to a national code

Ref country code: HR

Ref legal event code: PBON

Ref document number: P20100378

Country of ref document: HR

Effective date: 20121201

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20121201

REG Reference to a national code

Ref country code: AT

Ref legal event code: MM01

Ref document number: 465164

Country of ref document: AT

Kind code of ref document: T

Effective date: 20120530

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: BG

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20121231

Ref country code: AT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120530

Ref country code: MT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20130531

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: PL

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120530

REG Reference to a national code

Ref country code: PL

Ref legal event code: LAPE

REG Reference to a national code

Ref country code: PT

Ref legal event code: MM4A

Free format text: LAPSE DUE TO NON-PAYMENT OF FEES

Effective date: 20121130

REG Reference to a national code

Ref country code: ES

Ref legal event code: FD2A

Effective date: 20131021

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: RO

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120530

Ref country code: ES

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120531

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: TR

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120530

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120530

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120531

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: MT

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 20120530